Natural Cures For Prostate Cancer

The 21 Day Prostate Fix

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Overview

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The Molecular Pathogenesis of Human Prostate Cancer

Prostate cancer (PCA) has become the most commonly diagnosed cancer among men in the USA, with an estimated 189,000 cases diagnosed in 2002 (1). Encouragingly, over the past several years, increased use of serum prostate-specific antigen (PSA) screening has increased the fraction of men diagnosed with PCA confined to the prostate gland, leading to more effective use of surgery and radiation therapy for treatment, and to a decline in PCA mortality (2, 3). Despite these improvements, some 30,200 men will likely died of progressive metastatic cancer in 2002 (1). Furthermore, even though men with early PCA can be cured using surgery or radiation therapy, the side effects of treatment frequently include erectile dysfunction, urinary incontinence, or rectal irritation (4-6). New insights into the etiology of PCA are needed so that new strategies for its prevention can be developed. Recent studies of the earliest molecular steps in the development of human PCA have generated new evidence...

Benign Prostatic Hyperplasia BPH

Interestingly, the virtually ubiquitous process of BPH originates in the TZ of the prostate (62), and approximately 20 of all PCA occur in the TZ. Adenocarcinomas originating in the TZ are usually well-differentiated tumors with Gleason score generally lower than tumors from the PZ (63), and with architectural features that closely resemble foci of BPH. Over the years, the findings of BPH and PCA together in standard transurethral resection ofthe prostate (TURP) specimens has led to speculations that carcinomas may arise from hyperplastic lesions (64-66). Leav, et al. recently reported the possibility to define areas of transition from hyperplasia to carcinoma in six BPH nodules using AMACR (P504S), p63, or 340E12 antibodies (67). They reported enhanced AMACR expression in benign glands within cancer-containing nodules, as well as in BPH lesions adjacent to carcinomas and suggested that the up-regulation of the enzyme may precede morphological evidence ofneoplastic transformation....

Establishment of Models for Studying Prostate Cancer Cell Progression

Isolate A-insensitive cells, named IS cells. IS cells express very low levels of AR and are not stimulated or suppressed by A in the culture medium (Figure 2). These cells resemble human prostate PC-3 cells, since they do not have AR and can grow in the absence or presence of A.

Growth Suppression of Prostate Cancer Cells in Culture by Androgen

The cellular level of AR mRNA was 2-3 fold higher in the LNCaP 104-R1 and 104-R2 cells than in LNCaP 104-S cells. AR protein level increased 10-20 fold during this transition from A-dependent 104-S cells to A-independent 104-R1 or 104-R2 cells. The growth of both 104-R1 and 104-R2 cells, as well as CDXR cells in culture was suppressed by physiological concentrations (< 1 nM) of testosterone, 5a-DHT, or R-1881. Non-androgenic steroids, such as 5P-DHT, medroxyprogesterone, and cortisol, did not suppress 104-R tumor growth (24). AR in 104-R (R1and R2) cells was functional, since A induction of prostate-specific antigen (PSA) mRNA increased up to 20 times in these 104-R cells.

EGCG Suppression of Prostate and Breast Tumors

For a better understanding of the ability of green tea to control different forms of prostate tumors, we produced tumors in athymic mice by subcutaneously inoculating athymic mice with AR positive and A-dependent LNCaP 104-S cells, AR positive LNCaP 104-R2,104-R1 or CDXR cells whose growth is repressed by A, or AR negative PC-3 or IS cells whose growth is neither stimulated or repressed by A. We found that green tea EGCG (> 98 pure, 1 mg 20g body weight daily), injected intraperitoneally (ip), significantly inhibited the growth and rapidly (in 1-2 week) reduced the size of all types of human prostate tumors in athymic mice. Structurally-related catechins, such as epicatechin gallate (ECG) that lacks only one of the eight hydroxyl groups in EGCG, were inactive. Epicatechin (EC) and epigallocatechin (EGC) were also inactive (25). Since both A-dependent and A-independent prostate tumors respond to tumor suppression by EGCG. EGCG action was not related to modulation of A activity or due...

Expression of the Androgen Receptor in Prostate Tumor Models and Clinical Specimens

Among human PCA cell lines widely used, only LNCaP and MDA PCa 2a and 2b cells express AR. These cell lines are derived from PCA metastatic lesions (3,4). The reasons for AR down-regulation in other cell lines are not completely clear. It is assumed that some peptide hormones present in serum are responsible for down-regulation of the AR. For example, basic fibroblast growth factor is a potent inhibitor of AR expression (5). PC-3 and DU-145 cells, which do not express the AR, could be used for transient and stable transfections with AR cDNA. PC-3 cells stably transfected with the AR proliferate less rapidly than the cells transfected with an empty vector (6). Also, these cells are less invasive than their counterparts. AR expression is low in rat Dunning tumour sublines that rapidly metastasize (7). For this reason, it was believed for a long time that AR expression decreases during tumor progression. AR expression was studied with respective antibodies in clinical specimens obtained...

Challenges And Opportunities In Prostate Cancer

Prostate cancer presents specific opportunities for novel therapies such as cytokine gene therapy but also has specific challenges. Standard therapy for localized disease involves radical prostatectomy or radiation therapy which are often associated with significant morbidity (3). Despite a significant increase in the number of men diagnosed and treated with curative intent for localized prostate cancer, a considerable number of men develop local recurrence or distant disease following surgery or radiation performed with curative intent. Every year tens of thousands of men experience rising serum prostate-specific antigen (PSA) levels as a result of local recurrence after presumptive definitive therapy for prostate cancer because of the limited capacity to accurately determine the virulence and stage of presumed localized disease and the limited efficacy of surgery and or radiation therapy. Treatment options for these men are few and unproven (5) and the ability to predict...

Therapeutic Potential Of Adenovirus Mediated Interleukin12 Gene Therapy For Prostate Cancer

Key words Interleukin-12 prostate cancer orthotopic prostate cancer model in situ gene therapy metastasis Abstract Prostate cancer is characterized by extreme heterogeneity and multifocality of the primary tumour. The available clinical, pathological and molecular data suggest a lack of substantial clonal expansion at the primary site, yet metastatic progression of the disease often proceeds in an unpredictable and clinically undetectable fashion. Clinical and experimental data suggest that primary prostate cancer tumour cells can seed from relatively small tumour foci at the primary site. Overall, this unique biological pattern of progression presents unique and challenging problems regarding the detection and treatment of the disease. In general, currently used potentially curative therapies involve a single cytoablative modality (radical prostatectomy or radiation therapy) and are exclusively directed at the malignant cells within the prostate gland. At present the widespread use...

Open Simple Prostatectomy

This operation is reserved for BPH where the prostate weighs over 50-75 g. It is also appropriate where there is concomitant benign bladder disease requiring treatment such as a symptomatic diverticulum or a large stone. Potential risks are urinary incontinence, erectile dysfunction, retrograde ejaculation and urinary tract infection. The advantages over TURP are complete removal of the gland (therefore no recurrence) and no risk of dilutional hyponatraemia. However, there is an increased risk of intraoperative haemorrhage and a longer hospital stay. Previous prostatectomy, prior pelvic surgery and prostate cancer are contraindications to the operation. There are two possible approaches to enucleation of the prostate gland via open prostatectomy The retropubic approach allows excellent exposure and visualisation of the prostate and prostatic fossa during enucleation, ensuring complete removal and control of bleeding sites. There is minimal trauma to the bladder and precise transection...

Radical Prostatectomy

The three aims of this operation are cancer control, preservation of urinary continence and of sexual function. Two approaches are available the perineal approach was pioneered first and has the advantages of usually less blood loss and greater exposure of and access to the apex of the prostate, thus optimising removal of tumour from this critical margin and allowing precise transection of the urethra. However, its main disadvantage is that it does not allow access to perform a pelvic lymphadenectomy. Furthermore, a greater understanding of periprostatic anatomy and developments in surgical technique over the years have reduced blood loss and improved tumour clearance using the retropubic approach, to the extent that currently the perineal procedure is seldom performed. It may be indicated for small, low-grade tumours when pelvic lymphadenectomy can be safely omitted. Surgery should be deferred for at least six weeks following needle biopsy and twelve weeks following TURP to allow any...

Fibroblast Growth Factors And Their Receptors In Metastases Of Prostate And Other Urological Cancers

Key words Acid and basic fibroblast growth factor, prostate cancer, bladder cancer, renal cell carcinoma, invasion, metastasis, angiogenesis Abstract Theraputical options for advanced carcinoma of the prostate, bladder or kidney are limited. Therefore it is important to understand their invasion and metastasis, processes in which fibroblast growth factors play an important role. Basic fibroblast growth factor (bFGF) is expressed in androgen-insensitive prostate cancer cell lines PC-3 and DU-145 and in some clinical specimens. During progression of prostate cancer, the expression of the FGF receptor 2 isoform Illb, which preferentially binds keratinocyte growth factor (KGF) decreases and the expression of the isoform iiic, which preferentially binds bFGF increases. A similar phenomenon was observed in bladder cancer. Several FGFs are proposed to act as andromedins, proteins that mediate the effects of androgens in target tissues FGF-7 (KGF), FGF-8 and FGF-10. In prostate and bladder...

The Role Of Fibroblast Growth Factors In Prostate Cancer

Prostate cancer, which is the most commonly diagnosed malignant tumour in the Western world, could be cured with radical prostatectomy in its early stages. All other prostate tumours need to be treated with androgen ablation therapy. This therapy is only palliative and nearly all tumours progress to the therapy-refractory stage. Various experimental treatments for advanced disease have been tried with little success. Progression of prostate cancer involves alterations in expression and function of several positive and negative growth factors and their receptors, including those of the FGF family. The three peptides, aFGF, bFGF and, more recently, FGF-8 have been intensively investigated in prostate tumours with regard of their expression, interaction with the respective receptors, effects on growth in vivo and in vitro and regulation of angiogenesis and invasion. Importance of fibroblast-derived growth factors for prostate cancer was recognized in series of studies in which formation...

Dietary Prostate Cancer Risk Factors

There are at least seven major dietary macro- or micronutrients that are under intense scrutiny currently as dietary risk or protective factors (Table 15.1). Prominent among these is dietary fat or some component of fat (e.g., saturated fat), which first received attention as a mechanism to possibly explain the low risk in native Asian populations and the apparent rapid shift in risk upon migration of Asian populations to the United States. There are suggestive data that increased fat consumption is associated with higher circulating testosterone levels, providing a possible mechanism for a fat-prostate cancer relation ship.9 Both case-control and cohort data tend to support a relationship between fat consumption overall and prostate cancer risk 10,11 however, there are sufficient inconsistencies in the data, and the magnitude of risk even between extreme categories of estimated fat intake is sufficiently modest that fat is still not considered a proven prostate cancer risk factor....

Nondietary Prostate Cancer Risk Factors

Although most attention has focused on possible dietary risk or protective factors for prostate cancer as the most likely environmental risk factor category to explain the racial ethnic variation in incidence and the impact of migration on risk modification, other factors have also been evaluated over the past few decades. Among these, cigarette smoking and a history of any type of sexually transmitted disease are among the most reproducible. As there are no highly suspected carcinogens to the prostate found in cigarette smoke or any direct evidence of an infectious etiology of prostate cancer, it has been proposed that both of these risk factors might be indices of an androgenic profile associated with prostate cancer development.27 Smokers have higher circulating testosterone levels than nonsmokers.28 While there is no direct link between androgen levels and sexually transmitted diseases, androgen levels may be modestly correlated with indices of sexual activity.29 The substantial...

Risk Pathways For Prostate Cancer

Several molecular etiological pathways have been suggested for prostate cancer. Although androgen transactivation pathways clearly have received the greatest attention, others have been the focus of increasing research activity. Among the most prominent of these additional pathways are vitamin D metabolism, insulin-like growth factor (IGF) signaling pathways, and chemical carcinogenic pathways (Fig. 15.1). Hsing and Devesa39 developed an etiological model that integrates these pathways and incorporates many of the possible risk factors suggested for prostate cancer.39 With the availability in the past decade of polymerase chain reaction technology to study polymorphic variants in genes on a large-scale population basis, epidemiologists and molecular biologists have been afforded an opportunity to begin detailed evaluation of these pathways with special attention to the contribution of polygenic variation in prostate cancer development within and between populations. In the section...

Antiproliferative Effects On Prostate Cells

The exact mechanism of action of the antiproliferative effects of nettle extract on prostate cells has not been fully elucidated (Hirano et al 1994, Hryb et al 1995, Lichius & Muth 1997, Lichius et al 1999). Results from several in vitro studies suggest that several mechanisms are responsible. Reduced prostate cell metabolism and growth may result from inhibition of membrane ATPase activity and decreased binding capacity of sex hormone binding Prostate cancer One study found that a methanolic extract of stinging nettle roots slows the progression of prostate cancer in both an in vivo model and an in vitro system (Konrad et al 2000). One study involving 20 males with prostatic adenoma found that treatment for 7 days with nettle produced a significant drop in zinc level, thought to be a result of altering zinc-testosterone metabolism and diminishing zinc secretion in adenomatous tissue (Romics & Bach 1991).

Benign Prostatic Hyperplasia

Open studies involving a total of over 1 5 000 men with BPH have found significant improvements in prostate size, night-time urination, frequency of urination, urine flow and residual urine (ESCOP 1996-97). One double-blind study over 9 weeks of nettle extract in 50 men with BPH showed a significant decrease in sex hormone binding globulin and non-significant improvements in micturition volume and maximum urinary flow (Vontobel et al 1985) however, the authors explain that the results were due to inappropriate length and dosage of therapy. In another doubleblind, placebo-controlled study, treatment of 67 men with nettle produced a 14 improvement in urine flow and a 53 decrease in residual urine (Dathe & Schmid 1987). An open study of 30 patients with BPH showed that nettle root extract over an average of 3.5 months significantly decreased residual urine volume and increased maximal urinary flow in 50 of cases (Romics 1987). Marked subjective relief was also reported. A randomised,...

Hormonal Therapies For Metastatic Prostate Cancer

Due to the advent of screening with serum prostate-specific antigen (PSA) in the 1990s, the majority of prostate cancer cases are now diagnosed with clinically organ-confined disease. However, the assumption that earlier diagnosis would result in improved survival has not been ratified. In particular, approximately 30 of patients with organ-confined disease and 60 -80 of those with extraprostatic disease who receive potentially curative local therapy will eventually relapse.114 These data suggest that mi-crometastases are already present at the time of diagnosis. men with prostate cancer, targeting the andro-gen-signaling pathway remains the predominant form of treatment for patients who are either diagnosed with or subsequently develop metastatic disease (Fig. 16.4).4,5 A myriad of therapeutic agents that target the androgen-signaling pathway have been developed since the initial observation of Huggins and colleagues.115 The majority of these agents reduce circulating levels of...

Familial Aggregation Clues For Genetic Influences In The Etiology Of Prostate Cancer

Evidence of familial clustering of prostate carcinoma is well documented in many case-control studies.13-24 Three major conclusions can be drawn from these studies. First, estimates of the relative risk of developing prostate cancer are higher in first-degree relatives of prostate cancer cases compared to the general population. This increase of relative risk among relatives of prostate cancer patients has been demonstrated in several ethnic and racial groups, including African Americans, Caucasians, Hispanics, and Asians. Second, the risk of prostate cancer increases with increasing number of affected relatives. For example, in the study conducted by Lesko et al.,23 the odds ratio (OR) was 2.2 for subjects with a family history of prostate cancer in one relative and went up to 3.9 for subjects with a family history of two or more affected relatives. Third, the risk of developing prostate cancer among first- and second-degree relatives is negatively correlated with a decrease in the...

Linkage Studies Identifying Major Prostate Cancer Susceptibility Loci

Linkage analyses test for association between genetic markers at known chromosomal locations and disease phenotypes, to help identify and define specific chromosomal regions associated with prostate cancer. Genomewide screens for linkage have revealed several chromosomal regions that are likely to harbor prostate cancer susceptibility genes. Smith et al.7 reported the first genomewide screen for prostate cancer susceptibility genes and identified the first prostate cancer susceptibility locus, HPC1, at chromoso In a combined analysis of 772 HPC families by the International Consortium for Prostate Cancer Genetics,12 weak evidence of linkage to HPC1 was confirmed, with a small proportion (6 ) of families linked to this locus. A second prostate cancer susceptibility locus was reported to be at 1q42-43 (PCaP) in a genomewide screen by Berthon et al.8 Evidence of linkage to PCaP was found in 47 families of French and German origin, with a maximal two-point LOD score of 2.7. This locus is...

Androgen Levels And Risk Of Prostate Cancer

The role of the androgens in the process of car-cinogenesis to prostate cancer has been hypothesized and examined in many studies. Given that exogenous androgens can initiate and or promote prostate cancer in rodents and humans and that eunuchs rarely develop prostate cancer,58-61 circumstantial evidence implicates androgen levels in the etiology of prostate cancer. Further, a reduced risk of prostate cancer has been associated with certain hyperestrogenic-hypoandrogenic states,62 and estrogen therapy has a palliative effect in advanced cases.61 However, studies comparing hormone levels in men with and without prostate cancer have produced widely varying results.63,64 Several possibilities may explain these variations small sample sizes, analyses of hormone levels in blood collected after the diagnosis of cancer, nonrepresentative control subjects, no adjustment for other related hormone levels and hormone-binding protein levels, and no adjustment for other potential confounding...

Importance Of Androgens In The Carcinogenesis Of Prostate Cancer

The prostate is an androgen-dependent organ. Testosterone and androgen precursors freely diffuse into prostate cells. Through a coordinated network of enzymes, they can be rapidly and irreversibly converted to their reduced and more potent metabolic form, dihydrotestosterone (DHT). Both DHT and, to a lesser extent, testosterone bind to and induce the conformational change and activation of the androgen receptor (AR). The activated androgen-receptor complex then binds to the androgen response element (ARE) of androgen-responsive genes and initiates or inhibits their transcription.69-72 After fulfilling their role in transcriptional regulation, DHT and testosterone are oxidized to biologically inactive derivatives by another set of enzymes. The intracellular steady-state active androgen level, which is balanced by the availability of testosterone and dehydroepiandrosterone (DHEA), the formation of DHT, and the degradation of DHT and other androgens, is thought to be an important...

Genes In The Androgen Pathway As Candidates For Hereditary Prostate Cancer

A variety of genes are involved in the metabolic pathway of androgens and the mediation of the effects of androgens. Functionally important polymorphisms in genes that encode enzymes involved in androgen metabolism and transport may lead to differences in individual susceptibility to prostate cancer by altering the levels and effects of androgens, as proposed by Ross et al.75 (see Chapter 15) Thus far, studies of androgen-pathway genes and the risk of prostate cancer have focused mainly on sporadic prostate cancer. In addition, studies of HPC have primarily focused on the identification of novel major susceptibility genes. However, we cannot exclude the possibility that mutations (or polymorphisms) in androgen-pathway genes are involved in the etiology of HPC for the following reasons. First, given the biological relevance of andro-gens in the etiology of prostate cancer in general, it is possible that mutations in the andro-gen-pathway genes that significantly affect androgen...

Continuation Of Hormoneablative Therapy In Hormonerefractory Prostate Cancer

When prostate cancer becomes hormone-refractory, the decision to continue or stop LHRH agonist therapy is a difficult one. Evidence in the literature is contradictory. A review of Southwest Oncology Group cytotoxic chemotherapy trials in patients with hormone-refractory prostate cancer failed to define a difference in outcome based on continued LHRH therapy or previous orchiectomy opposed to cessation of prior LHRH-based treatment.138 However, another sizeable retrospective analysis (of patients treated with estrogens) suggested a modest benefit for continued hormonal ther-apy.139 Given the evidence in support of both cessation and continuation of LHRH agonist therapy once hormone-refractory prostate cancer is present, many clinicians opt to continue it after commencing chemotherapy. However, a case can be made for discontinuation of hormonal therapy in individual patients, depending on the side effects of the therapy balanced against a modest chance of disease acceleration after...

Prostate Cancer

The expansion of prostate cancer screening efforts in the United States during the mid 1980s, Endometrium Ovary Prostate Testis with emphasis on the prostate-specific antigen (PSA) assay, resulted in large increases in prostate cancer incidence through 1992 for white males and through 1993 for African-American males. Prostate cancer incidence increased 183 for white males and 136 for African-American males from 1973 to 1992, with the largest increases occurring from approximately 1988 through 1992. Rates from 1992 to 1998 show a reversal of this trend as incidence began to decrease in both white ( 25.4 ) and African-American ( 9.9 ) men (Table 1.2). The trend for prostate cancer in African-American and white men is similar, with the exception that it is delayed roughly 2 years in African Americans (Fig. 1.3), and the rate is approximately 1.5 times higher in African-American than white men. While the value of the PSA assay in identifying cases of asymptomatic prostate cancer and...

Vprostate Gland

The prostate gland is a collection of tubuloalveolar glands arranged in three concentric groups (mucosal, submucosal, and main), all of which empty into the urethra. The lumen of the tubuloalveolar glands contain deposits known as corpus amylacea. 1. The prostate gland secretes acid phosphatase, fibrinolysin, citric acid, amylase, and prostate'specific antigen (PSA). Serum levels of acid phosphatase and PSA are used in the diagnosis and management of prostate cancer. 2. DHT is the main mediator of prostatic growth. This is clinically important in benign prostatic hypertrophy because finasteride (a 5a-reductase inhibitor) can reduce DHT levels and shrink the size of the prostate gland. In addition, the action of DHT can be blocked by the receptor antagonist called flutamide.

Prostate Gland

The prostate, the largest accessory sex gland, is divided into several morphologic and functional zones The prostate is the largest accessory sex gland of the male reproductive system. Its size and shape are commonly compared to those of a walnut. The gland is located in the The peripheral zone corresponds to the main prostatic glands and constitutes 70 of the glandular tissue of the prostate. This zone is the most susceptible to inflammation. It is also the site of most prostatic carcinomas. The peripheral zone is palpable during digital examination of the rectum.

Prostate

Nd YAG lasers cause coagulation and have been used for trans-urethral laser ablation of the prostate in both the contact and the non-contact modes. In addition to coagulation of the prostatic tissue, adequate haemostasis is achieved as the coagulation extends into the blood vessels as well. The major disadvantages are, however, postoperative irritative voiding symptoms,49 and delayed unpredictable tissue sloughing. Vaporisation can be carried out with the CO2 or the Holmium laser. The Holmium laser at a wavelength of 2100 nm has both ablative and haemostatic properties. It has been used in combination with the Nd YAG laser to resect the prostate gland.50 The latest in bloodless laser surgery of the prostate is the high power KTP laser.51 This laser, although expensive, has been reported to have excellent Electrosurgical desiccation has also made a comeback in recent times and is a much more affordable energy source than laser. Thick loop resection offers the advantage of improved...

International Variation In Rates

The remarkable international variation in cancer rates, for many of the common cancers, such as breast and prostate, seemed to many to support the traditional view that endogenous hormones could not be the sole or primary cause. The low rates of breast, prostate, and several other cancers in Asian populations and their increase toward Western rates upon migration to the United States or Europe suggested that chemical factors or other environmental agents were the major causes of these cancers. While cigarette smoking was one such obvious chemical carcinogen, which would help to explain the international variation in lung and other smoking-related cancer sites, the most obvious cause of the other cancers seemed to be diet, other lifestyle factors, or unidentified environmental agents. In 1964, an expert committee of the World Health Organization stated that the categories of cancer that are thus influenced, directly or indirectly, by extrinsic factors . . . collectively account for...

Hormonal Carcinogenesis

Logically, identifiable murine mammary tumor virus or type B virus in human breast milk. We undertook our first epidemiological study of breast cancer in young women to address the possibility that a transmissible agent causing breast cancer might also exist in human breast milk. We were unable to substantiate this hypothesis as there was no evidence of excess risk associated with breast-feeding, and the excess familial risk of breast cancer was seen in both the paternal and the maternal family trees.12 However, we were very impressed with the evidence supporting a role for endogenous estrogen and the key importance of age at menarche as an expression of this susceptibility. Over the subsequent 25 years, we as well as others13,14 have continued to utilize epidemiological and sero-logical studies to accumulate evidence that endogenous estrogens played a pivotal role in breast cancer.15 At the same time, it became increasingly clear that endogenous hormones were likely to be important...

Current Trends In Hormonerelated Cancers

While we propose that genetic variation influences cancer risk in hormone-responsive tissue by programming endogenous hormone production, transport, and response, other lifestyle, diagnostic, and treatment factors appear to explain short-term trends in incidence and mortality. For example, trends in hormone-related cancers, such as breast, ovarian, prostate, and uterine cancers, show that incidence and mortality rates are influenced by several factors, including changing patterns of hormone-replacement therapy, oral contraceptive use, disease-screening practices, reproductive characteristics, and other lifestyle factors that vary over time and by racial ethnic group. During the past two decades, efforts to diagnose early stage cancer through screening have resulted in artificial increases in breast and prostate cancer incidence. The impact of changing reproductive factors and screening efforts on the incidence and mortality of each of these hormone-associated cancers is discussed...

Frank Z Stanczyk Philip Bretsky

In the human body, a balance exists between production and clearance of steroid hormones. Production of steroid hormones occurs de novo by biosynthetic pathways in specific endocrine glands, i.e., the adrenals and ovaries in women and the adrenals and testes in men. In addition, steroid hormones can be produced in peripheral (nonendocrine gland) tissues from circulating precursors that originate from the endocrine glands. Important sites of peripheral steroid hormone formation include the liver, kidney, breast, prostate, and sexual and nonsexual skin. After steroid hormones are secreted by the endocrine glands, they enter the systemic circulation, where they are mostly bound to proteins. The low-affinity bound and non-protein-bound (free) steroids, sometimes referred to as bioavailable steroids, are available for binding to steroid hormone receptors (progestogen, androgen, estrogen, glucocorticoid, mineralocorticoid) and if active, they exert a biological effect. Alternatively, they...

Formation of 5Androstene317Diol and Testosterone

Deficiency of 17fi-HSD type 3 causes a form of male pseudohermaphroditism referred to as 17fi-HSD deficiency,53 in which there is a deficiency in the biosynthesis of testosterone from androstenedione. The deficiency is confined to individuals with a 46 XY karyotype these individuals have testes, wolffian duct-derived male internal genitalia (with the exception of a prostate), female external genitalia, and gynecomastia.54,55

Metabolism Of Steroids

Steroid hormones undergo extensive metabolism by biochemical reactions in a variety of peripheral tissues, which include the liver, kidney, genital and nongenital skin, prostate, as well as adipose tissue. However, the liver is the primary site of steroid metabolism. Extensive steroid metabolism is due to the fact that steroids contain functional groups (e.g., double bond, ketone group, hydroxyl group) that are vulnerable to reduction or oxidation. Reduction of double bonds and ke-tone groups gives rise to hydrogens and hydroxyl groups that are in either the a or 3 orientation. Consequently, multiple isomers of a metabolite can be formed, as with progesterone metabolites. In addition to steroid metabolism involving oxidation reduction reactions, estrogens are especially vulnerable to hydroxylation reactions, which may occur on most of the carbons of the estrogen molecule. A third important source of steroid metabolites results from conjugation reactions. For a steroid to be eliminated...

AHydroxysteroid Dehydrogenases

Salts using gel-filtration chromatography of human liver cytosol.96 Subsequently, the enzyme was purified and its gene cloned and identified as 3a-HSD type 3.95 The gene is expressed in multiple tissues, including the liver and hormone-responsive tissues such as the prostate and breast.97 The AKR1C2 enzyme has high affinity for DHT and may be the predominant 3a-HSD that reduces DHT in the prostate. Although the AKR1C3 enzyme was originally identified as 3a-HSD type 2, it has low affinity for DHT and is currently considered to be 17jS-HSD type 5.98 Finally, the AKR1C4 enzyme, originally identified as 3a-HSD type 1, has the highest affinity for DHT but has been identified only in the liver.99

Vitamin D3 and Thyroid Receptors

The vitamin D3 receptor is involved in bone mineralization and calcium deposition in response to levels of 1,24-dihydrotachysterol (produced by the liver and kidney), as illustrated by kindred studies of mutations within the human VDR gene (Tables 3.6, 3.7).320 These mutations fall into two classes point mutations within the DBD that interfere with vitamin D-dependent transcription and mutations that affect ligand binding, rendering individuals insensitive to the actions of vitamin D3. Both mutations result in clinical phenotypes of general vitamin D3 resistance, including hypocalcemia and rickets.359 As a dimerization partner with RXR, VDR is also a candidate for hormone therapy in certain cancers. For example, activation of VDR in breast, lung, prostate, and colon tumors can have an-tiproliferative effects, which may influence RXR activity in these cells.360 Additionally, VDR can activate the cyclin-dependent kinase inhibitor

Familial Clustering Of Hormoneresponsive Cancers

Multiple large studies8 indicate that the risk of the most common hormone-responsive cancers (breast, prostate, and ovary) is significantly influenced by inherited differences in genome sequence. Specifically, the MZ twin of a patient with cancer is two to three times more likely to get the same cancer than a DZ twin. These studies suggest that 27 -57 of the variation in population risk is due to gene effects and the remainder to non-genetic (environmental and random) factors.9,10 While these studies show that inherited factors play a causal role, they also demonstrate that genes are far from the whole story in MZ twins, the rate of concordance for prostate cancer is on the order of 25 , showing that even genetically identical people can have very different outcomes with regard to can-cer.9,10 Moreover, in most cases, the genetic contribution is not attributable to a single gene (which would produce a recognizable mendelian pattern of inheritance) but rather must be divided among a...

Linkage Analysis in Families

Because linkage analysis is unbiased and genomewide, it represents a critical starting point for any study of disease genetics. This approach has been used successfully to identify BRCA1 and BRCA2, implicated in breast and ovarian cancers.5,6 Although linkage studies have implicated several chromosomal regions in prostate cancer,34-39 only two genes have been identified to date. ELAC2 (HPC2) was identified in 2001,38 with both rare and common mutations that showed association to disease, although the consistency of this association remains unclear.40-42 Mutations in RNASEL were proposed (via positional cloning) to be responsible for a subset of familial cases of prostate cancer.43 While these are exciting developments, it is not yet clear whether these genes or the pathways they identify play a significant role in the inherited basis of the common forms of these diseases.

Family History and Inherited Susceptibility

Although BRCA1 and BRCA2 are often described together, there are important epi-demiological distinctions between them. The BRCA1 gene has been associated with increased risk of ovarian cancer, while BRCA2 has been suggested to play a role in male breast cancer and possibly other cancers, such as pancreatic and prostate. The BRCA1 gene is associated with an early age at onset, but this is less clear for tumors associated with BRCA2. The histology of BRCA1- and BRCA2-associated tumors differs from sporadic cases and from each other.

Hydroxysteroid Dehydrogenases 1 And 2 In Other Tissues

There are few data on the expression of 17HSD1 and 17HSD2 in postmenopausal en-dometrium and endometrial carcinoma. Antibodies against 17HSD1 have revealed the enzyme in about 50 of carcinoma specimens.65 There was marked heterogeneity among 17HSD1-positive malignant tissue specimens staining intensity varied greatly, showing both stained and unstained malignant epithelial cells.65 In endometrial cancer cell lines, very little type 1 activity has been detected, while some cell lines have shown high type 2 enzyme-like activity and expression of 17HSD2 mRNA.56 Of male sex steroid target tissues, 17HSD2 has been detected in normal and malignant prostate. Higher expression of 17HSD2 has been detected in benign prostatic hyperplasia compared with prostatic carcinoma.66 PC3, a prostate cancer cell line, also expresses 17HSD2.56

Risks Of Developing Cancer

Male carriers of mutations in BRCA1 2 are also at increased risk of developing cancers. The lifetime risk of breast cancer in a male carrier of a mutation in BRCA2 is about 5 only a few cases of male breast cancer in BRCA1 families have been reported. Male carriers of BRCA1 2 have a higher incidence of cancer of the prostate the lifetime risk has been estimated to be 6 in BRCA1 carriers9 and 6 -14 in BRCA2 carriers by age 74 (the population risk being 2 at this age).10,11 There is a 6 risk of colon cancer in BRCA1 carriers.9

Management of the Unaffected Carrier

Male carriers are at increased risk of developing cancer of the prostate, as previously mentioned. Targeted screening in first-degree relatives of brother pairs with the disease demonstrated a higher detection rate of prostate cancer than expected however, whether there is a reduction in mortality is uncertain.25 A study of screening in BRCA1 2 carriers by annual measurement of prostate-specific antigen and rectal examination from 50 to 69 years is being proposed (R.A. Eeles, personal communication).

Androgen Transactivation Pathways

Androgens play a critical role in normal and abnormal prostate development. Studies of androgens and prostate cancer go back nearly 60 years. The pioneering work of Huggins in this area was rewarded with a Nobel prize. Substantial epi-demiological data support a critical role for an-drogens in prostate cancer etiology.2,3 Prostate cancer development is absent in men with marked androgen deficiency, such as eunuchs, or men with markedly reduced androgenization of the prostate, such as those with constitutional absence of 5a-reductase enzyme activity in whom the prostate remains a vestigial organ. Normal prostate development is induced by de- Ross and colleagues3 introduced the concept of a polygenic etiology of prostate cancer related to multiple functional polymorphic variants in genes involved in androgen biosynthesis, transport, activation, and metabolism. They proposed that each such variant might have only a minor impact on androgen transactivation and, therefore, on prostate...

T187m R227q F234l F194l

Tein, others resulted in either increases or decreases in enzyme kinetics. One in particular, an alanine-to-threonine substitution at codon 49 (A49T), resulted in a substantial increase in enzyme activity. Although uncommon in healthy control men, the Reichardt group assessed its possible role in prostate cancer etiology in a multiracial nested case-control study because of its substantial impact in vitro. In both African-American and Latino men, the A49T polymorphism was associated with substantial increases in prostate cancer risk, especially for advanced disease at presentation relative risk (RR) 1.5 for localized and 7.1 for advanced disease, respectively, in African Americans, p 0.001 for the latter association RR 1.7 for localized and 3.6 for advanced disease, respectively, among Latinos, p 0.043 for the latter association . The contribution of the A49T mutation in prostate cancer predisposition worldwide is uncertain increased incidence of the A49T mutation has been reported in...

Insulinlike Growth Factor Signaling Pathways

There is growing interest in the role of growth factors in prostate cancer development as these proteins can play important roles in regulating cell proliferation in the prostate. Particular attention has been focused on IGF-I and its binding proteins as prospective studies of circulating levels of IGF-I have suggested that individuals with high levels, especially when combined with low levels of binding proteins, may be at high risk of prostate cancer.76,77 Moreover, IGF-I activity may be one mechanism by which multiple possible etiological pathways are joined, including vitamin D pathways and androgen signaling, as both vitamin D analogues and castration can upregulate IGF-I binding proteins.78,79 As described above, an important androgen-regulated gene, the PSA gene, encodes a protease that can cleave IGF-I from its binding protein, leading to increased IGF-1 bioavailability, thus offering another possible connection between etiological pathways. Animal models are consistent with...

Wayne D Tilley Grant Buchanan Gerhard A Coetzee

The androgen-signaling axis is the principal regulator of the development, function, and growth of the prostate gland and plays a vital role in prostate cancer predisposition and progression. The major components of this axis include the biosynthesis and transport of testosterone to target tissues, where it is converted to the more active metabolite 5a-dihydrotestosterone (DHT) maturation of the androgen receptor (AR) to a ligand-binding-competent form nuclear import and the subsequent transcriptional regulation of AR target genes. The AR, which is the pivotal component of androgen signaling, is a member of the superfamily of nuclear transcription factors that regulate a diverse range of cellular functions by providing a direct link between signaling molecules and gene transcription.1-3 The AR is unique among nuclear receptors (NRs) in that a strong constitutive transactivation function involving at least three overlapping regions of the N-terminal domain (NTD) is responsible for...

Androgen Receptorassociated Proteins

Chang and colleagues63 identified several AR-associated (ARA) proteins that interact with either the AR LBD (ARA70 RFG ELEI, ARA55, ARA54) or the AR NTD (ARA24, ARA160 TMF). The AR N-terminal interacting protein (ARA160), also known as TATA element mod-ulatory factor, cooperates with ARA70 to enhance AR activity. Another AR NTD interacting protein, ARA24, interacts with the poly-Q tract. Binding of ARA24 is decreased by expanding the polyQ length within the AR NTD, the latter being inversely correlated with the transcriptional activity of AR. Additional studies have demonstrated that AR and some select AR coactivators, such as ARA70 and ARA54, can interact with CBP and PCAFs that have histone acetyltransferase activity for assisting in chromatin remodeling. Wang et al.64 identified a new ARA protein, ARA267-a, that interacts with both the AR DBD and LBD. Unlike other coregulators, such as CBP, ARA267-a exerts little influence on AR N-C interactions but enhances AR transactivation in a...

Ligand Independent Activation

Binding of high-affinity androgenic ligands is not the only mechanism by which the AR can activate target gene sequences. There is an accumulating body of evidence that the AR can be activated in in vitro systems in the absence of native ligand by growth factors (keratinocyte growth factor, insulin-like growth factor I, and epidermal growth factor), cytokines interleukin-6 (IL-6) , protein kinase A, and overexpression of the tyrosine kinase receptor HER2 neu.9,72-75 The mechanism(s) that causes LIA of the AR is best understood in the case of HER2 neu overexpression. HER2 neu is a transmembrane gly-coprotein member of the epidermal growth factor receptor family and is overexpressed in carcinomas of the breast, ovary, stomach, and prostate.76 Overexpression of HER2 neu in androgen-responsive prostate cancer cell lines enhances AR transactivation of androgen-regulated genes such as PSA in a ligand-independent manner and increases cell survival during androgen deprivation.75 HER2 neu...

Androgen Receptor CAG Repeat

In 1992, Edwards et al.24 reported the allelic frequency distribution of AR CAG repeat size in different U.S. racial ethnic populations as part of a larger survey of genetic variation in a series of different trimeric and tetrameric tandem repeats. Among African Americans, the frequency of AR alleles with fewer than 22 CAG repeats was 65 compared to 53 in Caucasians and 34 in Asian Americans. On the basis of these observations, Coetzee and Ross78 hypothesized that AR CAG repeat length might be associated with the higher risk of prostate cancer in African Americans and the intermediate and low risks in In 1995, the same investigators directly tested this hypothesis in a pilot case-control study comprising 68 prostate cancer patients and 123 control subjects.79 In agreement with Edwards et al.,24 there was a prevalence of short AR CAG alleles in African-American vs. Caucasian and Asian-American controls. In addition, modest, though not statistically significant, enrichment of short AR...

Androgen Receptor And Localized Disease

The role of AR in the progression of clinically localized prostate cancer has only recently been addressed.103,104 Henshall et al.103 reported that AR was expressed in more than 70 of the tumor cells in localized prostate cancer but that there was loss of AR immunoreactivity in the ad jacent peritumoral stroma, which was associated with earlier relapse after radical prostatectomy. Sweat et al.104 found no association between AR expression and disease progression in a highly selected cohort of tumors with a Gleason score of 6-9. In our laboratory, the level of AR protein in tumor foci determined by video image analysis was a strong predictor of the risk of relapse following radical prostatectomy (unpublished observations). While further studies are necessary to determine how AR influences disease progression in clinically localized prostate cancer, a number of mechanisms have been identified in prostatic tumors that potentially explain the increase in levels of AR immunostain-ing...

Androgen Receptor Levels

Initial studies using both androgen-unrespon-sive Dunning rat adenocarcinoma and human prostate cancer cell lines suggested that loss of AR mRNA and protein could be a mechanism to explain the failure of androgen-ablation therapies.129,130 Subsequent immunohistochemical studies of clinical prostate cancer demonstrated that the AR is expressed in essentially all metastatic tumors, including those that continue to grow following androgen ablation.131-137 Other studies have shown that the AR in recurrent, hormone-refractory prostate cancer is expressed at levels similar to those in androgen-dependent prostate tumors.138 Recent studies using the recurrent CWR22 xenograft model and its derived cell line, CWR-R1, as well as the LNCaP C4-2 cell line derived from LNCaP cells after prolonged periods of culture in the absence of androgen suggest that the AR is expressed at similar levels in both an-drogen-dependent and recurrent tumors but is more stable in recurrent tumors in the absence of...

Cell Lines A Xenografts A Tramp Model

Figure 16.5 Collocation of androgen receptor (AR) gene mutations in prostate cancer (PCa). The majority (80 ) of AR gene mutations identified in clinical prostate cancer collocate to discrete regions within the receptor N-terminal domain (NTD) and ligand-binding domain (LBD) as indicated. Mutations in each of these regions (PolyQ, polyglutamine repeat LIAF, ligand-independent activation function QPIF, a tetrapeptide at the boundary of the hinge and LBD SS, signature sequence AF2, activation function 2) have been shown to result in changes to receptor ac tivity, which could explain the outgrowth of prostate cancer cells containing these mutations during androgen ablation therapies. The position of mutations identified in human prostate cancer cell lines, xenografts, and the transgenic adenocarcinoma of the mouse prostate (TRAMP) model are indicated. Hormonal treatment of TRAMP mice drives the selection of AR gene mutations to either the NTD (7 9 castrate mice vs. 0 6 intact animals) or...

Ligandbinding Domain Variants

In the LBD, mutations collocate to (1) the signature sequence, a conserved 20-amino acid region of NRs involved in ligand recognition and specificity 154 (2) AF-2, a binding site for the p160 cofactors and (3) a region at the boundary of the hinge and LBD containing a 4-amino acid tetrapeptide (668QPIF671), which may define a protein-protein interaction surface (Fig. 16.5). Many of the AR gene mutations identified in the LBD of the AR in the TRAMP model, xenografts, and cell lines occur in the same three regions as mutations in clinical prostate cancer (Fig. 16.5). For example, a Phe-Ile671 mutation identified in an intact TRAMP mouse colocates to the 668qpiF671 tetrapeptide with mutations identified in human prostate cancer.8 Mutations of the AR gene identified in both clinical prostate cancer and TRAMP tumors in this region exhibit a two- to fourfold greater transactivation activity in response to DHT, nonclassical ligands, and hy-droxyflutamide compared to wtAR,8 without altering...

Dnabinding Domain Variants

In addition to the above observations, five somatic missense mutations have been identified in clinical prostate tumors that collocate to a 14-amino acid region at the carboxyl-terminal end of the first zinc finger motif in the DBD of the AR.146,149 The effect of each of these mutations is unknown, but none of the codons in which they occur has been reported to contain mutations that cause receptor inactivation in the clinical syndrome of androgen insensitivity. Mutations in the AR DBD selectively affect the transactivation and transrepression functions of the AR on different promoters despite reduced DNA-binding ability156,157 and may represent a predisposing factor for male breast cancer.158 Due to the high ho-mology of the DBD across members of the NR superfamily, the cell and promoter specificity of different receptors is, in part, mediated by only a few changes in DBD sequence.159 Mutations in the DBD may result in AR variants that bind to response elements normally specific for...

Aminoterminal Transactivation Domain Variants

Nearly half of the AR gene mutations identified in clinical prostate cancer are located in the NTD of the receptor. Mutations of the AR gene in this domain have also been identified in the TRAMP model, and analogous to the observations for the LBD, these mutations cluster with those identified in clinical prostate cancer to discrete regions within the NTD that are implicated in receptor function. The main regions of colocation in the NTD are (1) within and adjacent to the polyQ tract (codons 54-78), which, as discussed above, has been implicated in modulating receptor activity and prostate cancer risk, and (2) a region amino-terminal to the DBD (codons 502-535) known to modulate the trans-activation capacity of the receptor in both a ligand-dependent and ligand-independent manner (i.e., LIAF) (Fig. 16.5).165,166 Somatic contractions in the CAG repeat of the AR gene, which potentially increase AR activity in a subpopulation of cells and thereby contribute to disease progression, have...

Altered Interaction with Coregulatory Molecules

Observed in recurrent tumors from CWR22 human prostate xenografts and clinical prostate cancer, increases AR transactivation capacity at physiological concentrations of nonclassical lig-ands (adrenal androgens, estradiol, and progesterone). Overexpression of p160 coactivators, especially TIF2, favors an interaction between the coactivator and AF-2 in preference to formation of an N-C interaction (between an LxxLL-like motif in the NTD and a hydrophobic interaction surface that overlaps with AF-2). Overexpression of TIF2 could therefore result in the recruitment of TIF2 to AF-2 by low-affinity steroids, resulting in inhibition of N-C interaction and derepression of LIAF in the NTD. Characterization of the functional relationship between the AR and ARA coregulators by Yeh and colleagues174,175 has shown that ARA70 and ARA55 can enhance the androgenic effects of 17j6-estradiol and hydroxyflutamide, the latter an antiandrogen commonly used in the treatment of metastatic prostate cancer....

Ligand Independent Activation of the Androgen Receptor

Another potentially important mechanism contributing to the failure of androgen ablation is LIA of the AR. Aberrant expression of growth factor receptors also contributes to the development and progression of prostate cancer.10,151 HER2 neu (c-erbB-2), a transmembrane glyco-protein member of the epidermal growth factor receptor family, is overexpressed in carcinomas of the breast, ovary, stomach, and prostate.176-179 Unlike other epidermal growth factor receptor members, HER2 neu has intrinsic tyrosine ki-nase activity and mediates signal transduction in the absence of ligand.180 HER2 neu expression is increased in hormone-refractory prostate tumors compared to earlier stages of disease.76,181 Overexpression of HER2 neu in androgen-re-sponsive prostate cancer cell lines enhances AR transactivation of androgen-regulated genes such as PSA in a ligand-independent manner and increases cell survival during androgen dep-rivation.9,74 Although the mechanism involved in HER2 neu modulation of...

Baoli Chang Aubrey R Turner William B Isaacs Jianfeng Xu

Prostate cancer is the most frequently diagnosed noncutaneous cancer in men in Western countries. Both genetic and environmental factors have been implicated in the etiology of this disease. A genetic component of prostate cancer has been suggested by both twin and segregation studies.1-6 About 9 of all prostate cancer cases have been proposed to be due to mutations in prostate cancer susceptibility genes,1 and the overall effect of heritable factors has been estimated to be higher for prostate cancer than for other common can-cers.6 So far, linkage studies of prostate cancer families have provided evidence for several major prostate cancer susceptibility loci.7-12 In addition to major gene effects, common polymorphisms that result in minor quantitative and qualitative functional differences in gene products most likely modify the risk of prostate cancer. As a hormone-related cancer, genes involved in the androgen-metabolism pathway are particularly compelling candidates for prostate...

Twin Studies Dissection Of Genetic Factors From Environmental Influences

Familial aggregation may be due to genetic or shared environmental factors. Twin studies can be used to estimate the contribution of inheritance to the familial aggregation of a trait or disease by comparing the similarities (concordance rate) of a trait or disease in monozygotic (MZ, genetically identical) and dizygotic (DZ, sharing on average 50 of genetic material) twins. In a registry of 4840 male twin pairs in Sweden, 458 cases of prostate cancer were identified. There were 16 concordant pairs among 1649 MZ twin pairs (1 ) but only six concordant pairs among 2983 DZ twin pairs (0.2 ). The greater concordance rate seen in MZ twins compared to DZ twins is attributed to a greater degree of shared genes.2 A second twin study, conducted in the United States, showed similar results.4 Among 1009 twin pairs identified from a national twin registry, a significantly higher concordance rate was observed among MZ twins (27.1 ) compared to DZ twins (7.1 ). It was estimated that genetic...

Segregation Analysis Evidence Of Major Susceptibility Genes

The evidence from twin studies and family studies supports the importance of genetic factors in the development of prostate cancer. However, these studies cannot infer the genetic model of inheritance. To identify a specific inheritance model of hereditary prostate cancer, complex segregation analysis can be used. So far, there are four complex segregation analyses of prostate cancer that support an autosomal dominant inheritance model for prostate cancer susceptibility, especially for early-onset disease.1,3,5,29 A prostate cancer susceptibility gene was estimated to be rare in the general population, with a frequency of about 0.0031 to 0.006.5 The pen-etrance of such a rare susceptibility gene was estimated to be 88 by age 85 for carriers and 3 -5 for noncarriers. However, other inheritance models have been suggested for prostate cancer. The segregation analyses by Schaid et al.5 confirmed that dominant inheritance was the best-fitting model for families with early-onset prostate...

George V Thomas Charles L Sawyers

Androgen-independent prostate cancer is incurable and is responsible for the majority of cancer-related deaths. The intriguing question is how a cancer that is initially exquisitely sensitive to an-drogen-ablation therapy becomes universally refractory to all available forms of such therapy. Both normal and cancerous prostate cells are dependent on androgens, mainly in the form of testosterone and dihydrotestosterone (DHT), to promote proliferation and inhibit apoptosis.1-3 Androgen mediates its biological actions through the androgen receptor (AR), a ligand-activated transcription factor of the steroid nuclear receptor superfamily (see Color Fig. 18.1 in separate color insert).4-6 Androgen-ablative treatment modalities rely on either surgical or medical castration, the latter usually administered via luteinizing hormone-releasing hormone (LHRH) analogs (termed monotherapy when used singly) and AR antagonists (termed total androgen-ablative therapy when used in combination).7,8...

Androgens And The Androgen Receptor

The testis, which produces testosterone, and adrenal glands, which produce androstenedione, dehydroepiandrostene, and dehydroepiandro-stene sulfate, contribute to the bulk of circulating androgens. These are converted in the prostate or peripherally by 5a-reductase to DHT, which is approximately 10 times more active than testosterone.13 Androgens affect both the epithelial and mes-enchymal components of the prostate, regulating growth and differentiation and inhibiting apoptosis. In murine prostates, castration results in glandular atrophy and involution, which is re versed by androgen replacement. The histolog-ical hallmarks of androgen-ablation therapy in the human prostate are atrophy, vacuolation, squamous and transitional cell hyperplasia, and basal cell hyperplasia.14,15 Basal cells are considered to harbor the stem cells of the prostate, not requiring androgens for survival but at the same time able to proliferate and differentiate in response to androgen exposure. In contrast,...

Androgen Receptor Overexpression

Can the initiation, development, and progression of prostate cancer be attributed to AR overexpression by virtue of its positive effects on proliferation and its antiapoptotic effects Stanbrough et al.,35 using the rat probasin promoter to overexpress the murine AR transgene in mice, reported increased proliferation rates in the ventral and dorsolateral prostates of transgenic mice compared to wild-type littermates.35 In addition, older mice developed prostatic intraepithelial neoplasia, a precursor lesion to prostate cancer. Hence, at least in mice, it appears that AR overexpression can initiate the development of precursor lesions but does not cause invasive cancer. In human prostate cancer, the implication of AR overexpression in AI progression has come from the finding of AR gene amplification in tumors. Interestingly, AR amplification appears to be a feature of tumors that have been previously treated with androgen-ablation therapies and is very rarely found in untreated prostate...

Androgen Receptor Mutations

The AR gene maps to the X chromosome, thus rendering all mutations dominant in prostate cancer. Germ-line inactivating mutations of AR are well documented in the androgen-insensitivity syndrome.6,38 Similar to AR amplification, the frequency of AR mutations is rare in untreated prostate cancer. In contrast, AR mutations have been detected in as high as 50 of advanced and metastatic tumors, indicating that mutations are much more common in AI cancers.39,40 These mutations may be present from the onset of the cancer (but remain undetectable due to the low sensitivity of the available assays) or may be acquired. In either case, it appears that these mutations gain prominence under the selective pressure of androgen-ablative therapy, as seen with AR amplification. Evidence for AR mutations in prostate cancer first surfaced when AR was studied in the metastatic prostate cancer cell line LNCaP. Sequencing results uncovered a single missense point mutation in codon 877 of AR, resulting in a...

Her2Neu Receptor Tyrosine Kinase

The Her2 Neu oncogene encodes a transmembrane glycoprotein with a tyrosine kinase domain that is structurally related to the EGFR family of receptors. It has intrinsic kinase activity and is able to activate receptor-mediated signal transduction when overexpressed. Her2 Neu is amplified and overexpressed in 20 -30 of breast and ovarian cancers.53,54 Overexpression in breast cancer is associated with poor prognosis. With the development of humanized monoclonal anti-Her2 Neu antibody as a viable treatment option, the significance of targeting specific receptor tyrosine ki-nases has gained clinical prominence.55 However, studies of Her2 Neu expression in human prostate cancer have revealed conflicting results, with different groups reporting differing levels of gene copy amplification and protein expression.56-61 Her2 Neu is expressed in normal prostatic epithelial cells, and its putative ligand, heregulin, is expressed in the stroma, suggesting a paracrine mode of growth factor receptor...

Phosphoinositide 3KinaseAKT Pathway

Sor gene PTEN has focused a high degree of interest on this pathway. The PTEN gene possesses both lipid and protein phosphatase activity. In the context of the PI3K pathway, PTEN removes the 3-phosphate from PtdIns(3,4,5)P3, thus blocking or dampening the PI3K-AKT pathway. The PTEN gene localizes to chromosome 10q23. Loss of heterozygosity of this region has been found in 20 -60 of prostate cancers, with more advanced metastatic tumors exhibiting higher rates.69-71 Loss of protein expression (as seen by lack of immunohistochem-ical staining for PTEN) is found predominantly in tumors of higher Gleason grade and stage, thus correlating PTEN loss with more aggressive tumors.72 Mice heterozygous for PTEN as well as conditional PTEN knockouts (pure PTEN knockouts result in embryonic lethality) develop diffuse prostatic hyperplasia and eventually cancer.73-75

Hypophysectomy and Adrenalectomy

Surgical hypophysectomy and adrenalectomy have been used to treat prostate cancer. However, they provide no clear therapeutic advantage over castration as first-line therapy. In patients relapsing after castration, hypophysec-tomy and adrenalectomy are reported to result in symptomatic improvement in around 20 of patients but are not clearly superior to second-line hormonal strategies.24 They have the disadvantage of surgical morbidity. In particular, an added potential side effect of hypophysectomy is central abolition of adrenocorticotropin and

AReductase Enzyme Inhibitors

Given the pivotal intracellular role of 5a-reduc-tase in androgen metabolism, it has been postulated that inhibition of this enzyme with agents such as finasteride has the potential to inhibit prostate carcinogenesis and or induce regression in established prostate cancer.65,66 The recent demonstration that individuals with a germline 5a-reductase missense mutation that results in increased enzyme activity had a higher chance of developing prostate cancer adds weight to this hy-pothesis.67,68 In addition, the tumor expression of 5a-reductase is increased in high-grade and androgen-insensitive prostate cancer.69 Despite this, clinical evidence suggests that finasteride therapy does not inhibit the development or progression of prostate cancer70 and may result in unexpected toxicity when given with other hormonal thera-pies.71 Cote et al.,72 in a study conducted at the University of Southern California, showed that fi-nasteride did not inhibit the development of prostate cancer and...

Combined Androgen Ablation

Combined, or maximal, androgen ablation (CAB) has traditionally involved the combination of an LHRH antagonist (e.g., goserelin, leuprolide, or buserelin) or orchiectomy and a peripheral inhibitor of androgen action in target tissues (e.g., flutamide, nilutamide, bicalu-tamide, or cyproterone acetate). Labrie et al.33,77 suggested that nearly all prostate cancer patients experience an objective response to CAB. Subsequent studies have failed to replicate fully these initial observations. However, several important studies have come from the desire to compare CAB with single-modality hormonal therapy. A North American Intergroup trial evaluated 603 men with metastatic prostate cancer in a prospectively randomized placebo-controlled study of LHRH agonist therapy (leuprolide) with or without the peripheral androgen blocker flutamide.78 There was a statistically significant benefit of leuprolide with flutamide over leuprolide with placebo in time to cancer progression (16.9 and 13.8...

Timing Of Hormonal Therapy Early Versus Delayed Treatment

In detecting and monitoring advanced disease, the progressive introduction and widespread availability of nucleotide bone scanning, serum PSA estimation, high-resolution computerized tomography, magnetic resonance imaging, and positron emission tomography have increasingly resulted in earlier diagnosis of asymptomatic patients with minimal recurrent or metastatic disease. The duration between the first abnormality in one of these tests and the development of clinically symptomatic prostate cancer can be many years.97 On this basis, clinicians are confronted with a major stage shift of patients to an earlier time point in their cancer development, the phenomenon of stage migration. Patients with only a biochemical or minor imaging abnormality and no symptoms have a lower disease burden, longer natural disease history, and longer survival than patients with clinical symptoms. Earlier detection raises the question of whether earlier treatment improves outcome sufficiently to outweigh the...

Adjuvant And Neoadjuvant Hormonal Strategies

The widespread availability and use of serum PSA testing and outpatient prostate biopsy in the past decade have resulted in many more men being diagnosed with clinically localized or locally advanced prostate cancer. One result of this is that these men are undergoing therapies such as radical prostatectomy and radiation for early disease. While the efficacy of such interventions in altering outcome is debated, it is clear that monomodality local therapies yield intermediate cancer control in only a proportion of patients. The reason for this limited effect is complex but may relate to undetected micrometastatic disease beyond the surgical specimen or radiation field and or failure of local treatment due to inadequate surgical clearance (macroscopic surgical margin involvement) or cancer resistance to radiation. On this basis, a variety of strategies have been developed and tested with the aim of improving cancer control in patients undergoing therapy for clinically localized disease.

Neoadjuvant Hormonal Therapy

Neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy has not been shown to improve disease-free survival despite a 30 reduction in surgical margin involvement on pathological evaluation compared to those not receiving such therapy before proceeding to sur-gery.100-105 The degree of fall in serum PSA seen in these patients does not predict the likelihood of positive margins at surgery.106 Patients with either clinical or pathological extension of prostate cancer through the prostatic capsule (stage T3) do poorly with NHT and radical prostatectomy.107-110 Conversely, neoadjuvant and or concurrent hormonal therapy improved outcome in patients undergoing radiation therapy in two randomized trials (Fig. 19.3).111,112 Studies comparing cancer control and morbid ity for radiation therapy combined with NHT and that observed for other treatments used in clinically localized prostate cancer are urgently needed. At present, NHT prior to planned surgery is not recommended outside a...

Adjuvant Hormonal Therapy

For patients with lymph node involvement at radical prostatectomy, continuous hormonal therapy is considered standard care in some centers. A series of non-randomized comparisons supported the use of indefinite therapy in the form of either LHRH agonists or orchidec-tomy.113-117 More recently, a randomized trial has demonstrated benefit from long-term LHRH agonist therapy for patients with lymph node involvement delineated at radical prostatectomy (Fig. 19.4).118 This study has been criticized for low power and early termination. Whether patients with pelvic lymph node involvement can be treated with transient adjuvant therapy instead of indefinite hormonal therapy has not been determined. Whether long-term hormonal therapy is justified in patients with other adverse pathological findings at radical prostatectomy, such as seminal vesicle involvement or extensive extracapsular disease, remains to be determined. Despite widespread use in patients with these adverse pathological...

Side Effects Of Hormonal Therapy Similarities And Differences

Hormonal therapy for prostate cancer eventually produces decreases in libido and potency in virtually all patients regardless of the modality used.34,124 Additional side effects include lethargy, depression, anorexia, breast swelling with or without tenderness, hot flashes, anemia, and osteoporosis with potential for pathological fracture.14,125-130 Most side effects, including impotence and infertility, are slowly reversible with cessation of therapy. However, reduced bone mineral density often does not reverse after prolonged hormonal suppression. There is a consensus that irreversible changes occur more often after suppression of longer than 18-24 months.

Intermittent Versus Continuous Therapy

Intermittent cessation of hormonal therapy may improve long-term outcome by preventing the development of mutations in an environment of androgen deprivation or by impeding the evolution to AR overexpression that is a feature of prostate cancer progression.132 To attenuate the side effects of hormonal suppression, recent investigative strategies have been designed to determine whether intermittent cessation of CAB improves QOL without compromising cancer control. The answer to this question awaits the outcome of a number of prospective randomized studies currently in accrual phase. Experimental and some clinical evidence suggests that tumors that respond initially and then progress when hormonal therapy is stopped will usually respond to further androgen deprivation.133,134 Preliminary evidence suggests that interruption of hormonal therapy can improve QOL.135 However, studies initiated in Canada in 1995 have largely been undertaken in patients with PSA relapse rather than patients...

Secondline Antiandrogen Therapy

The European Organization for Research and Treatment of Cancer randomized 201 patients to either prednisolone 5 milligrams four times per day or flutamide 250 milligrams three times per day following symptomatic progression of prostate cancer treated with initial medical or surgical castration.140 The investigators concluded that treatment with prednisolone or flu-tamide leads to similar rates of progression and overall survival and no difference in subjective or biochemical response. A U.S. National Prostatic Cancer Project trial randomized 220 men with hormone-refractory prostate cancer after initial surgical castration to either flutamide or estramustine therapy and found no difference in response or survival between the two drugs.141

New Adrenal Aromatase Inhibitors

Given the efficacy but significant side effects of aminoglutethimide in prostate cancer progressing after castration, evaluation of newer aro-matase inhibitors with more specific sites of action and proven activity in breast cancer seems logical. Unfortunately, anastrozole,165 letrozole, and exemestane have produced negligible response rates in early-phase pharmaceutical company testing. The reasons for this are complex but may result from the more selective inhibition of adrenal aromatase relative to other steroid pathway-metabolizing enzymes compared to aminoglutethimide. Specific aromatase inhibition will block production of estradiol and estrone from T and androstenedione, respectively, with decreased levels of circulating estrogens but potential for increased androgen production. Interestingly, the very lack of specificity that produces toxicity with aminoglutethimide may also account for its activity in prostate cancer because aminoglutethimide inhibits the generation of...

Strategies Incorporating Hormonal Therapy and Cytotoxic Chemotherapy

The benefit of cytotoxic chemotherapy for patients with hormone-refractory prostate cancer is now firmly established.171,172 Several attempts have been made to determine whether response to and duration of clinical remission from hormonal therapy can be improved by the early addition of cytotoxic chemotherapy. Generally, with the notable exception of a combination of estramustine with selected cy-totoxic drugs (see below, Estramustine in Combination with Cytotoxic Drugs), these attempts have met with limited success. The Southwest Oncology Group studied the combination of endocrine therapy (estrogens or or-chiectomy) with doxorubicin and cyclophos-phamide randomized against endocrine therapy alone with addition of the same chemotherapy regimen at progression.173 This trial accrued between September 1982 and October 1986. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63 ) compared to those on endocrine therapy alone (48 ), but this was not...

Estramustine in Combination with Cytotoxic Drugs

Ing oral ingestion, estramustine is preferentially taken up by and retained in prostate tissue and prostate cancer cells. As a single agent, estra-mustine has not demonstrated benefit over continued or alternate hormonal therapy in hormone-refractory prostate cancer.179 However, in combination with cytotoxic agents, estramustine appears to contribute to response.180-183 While the mechanism for this is unclear, the effect of estramustine may occur through a phase activation of prostate cancer cells so that they are more sensitive to subsequent or concurrent cytotoxic effects. Estramustine alters cellular microtubu-lar configuration and may have synergy with other drugs that act on microtubules, such as tax-anes (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine).181,184-186 Reports from phase I and phase II trials suggest that the combination of estramustine and docetaxel is well tolerated and produces a decrease of over 50 in serum PSA in around 50 of...

Angiogenesis Inhibitors

Angiogenesis inhibitors are now in clinical trials for a number of cancers. The clinical experience with these agents has been that toxicity is acceptable and a proportion of patients experience tumor shrinkage. However, a larger proportion of patients experience disease plateau with little change in the size of tumor deposits while on therapy.244 Complete response to angiogenesis inhibitors as single agents is rare. Early trials using antiangiogenesis agents are under way in prostate cancer with interesting early results in heavily pretreated patients.245,246 Given the static response to these agents in other cancers,244 further clinical trials are needed to determine whether this response is additive or syn-ergistic with other therapies in different phases of prostate cancer progression.

Metalloproteinase Inhibitors

Prostate cancer progression involves increased expression of selected matrix metallopro-teinases (MMPs) with decreased expression of tissue inhibitors of metalloproteinases (TIMP). In vitro experiments demonstrate that neoan-giogenesis by transformed prostate cells occurs concurrently with a decrease in TIMP-1 levels and an increase in MMP-2 and MMP-9 levels. This process is inhibited by the action of interleukin-10 and the bisphosphonate ale-dronate247,248 and stimulated by interleukin-8. In addition, synthetic metalloproteinase inhibitors have been shown to inhibit prostate cancer growth in model systems,249 while met-alloproteinase secretion is important in the formation of bone metastases.221 On this basis, exogenous metalloproteinase inhibitors may have the potential to improve the duration of re and bisphosphonates.253,254 Many other trials are under way using an array of other agents with MMP-inhibitory activity.255 Bis-phospho-nates have demonstrated a significant palliative...

Androgen Receptor Gene Mutations

The first indication that AR gene mutations might contribute to the failure of androgen-ablation therapies came from studies of the an-drogen-responsive human prostate cancer cell line LNCaP. The AR in LNCaP cells contains a single-amino acid substitution (Thr-Ala877), which facilitates inappropriate activation by glucocorticoids, progestins, adrenal androgens, estradiol, and the antiandrogen hydroxyflu-tamide.144,145 Subsequently, somatic missense mutations have been detected throughout the AR coding sequence at frequencies of up to 50 in advanced primary tumors and metastatic de-posits.10,146-149 These mutations consistently result in receptors that exhibit decreased specificity of ligand binding and enhanced receptor activation by androgens and non-classical ligands compared to wild-type AR (wtAR).150,151 More recently, in collaboration with Dr. Norman Greenberg (Baylor College of Medicine, Houston, TX), we reported the identification of AR gene mutations in the autochthonous...

Ronald K Ross Nick M Makridakis Juergen K V Reichardt

The epidemiology and etiology of prostate cancer are probably the least understood of any of the numerically major cancers. Although andro-gens have long been thought to play an important role in prostate cancer development, this remains unproven. While there is substantial indirect evidence for such involvement (reviewed below), direct evidence is still lacking. The epidemiology of prostate cancer is controlled by two risk factors, age and race ethnicity but there is no firm understanding of why these two factors play such a crucial role in modifying risk.

Conclusions

The development of a hormonal carcinogenesis model began over 100 years ago with the observation that ovarian function was related to breast cancer risk. Over time, it became apparent that hormones act as carcinogens by increasing cellular proliferation and thereby increasing the chance of random DNA copy errors. Through epidemiologic and serological studies, we observed that hormones are key determinants of cancer in several hormone-sensitive tissues, including the prostate, breast, endometrium, ovary, and possibly thyroid and testes. While findings from studies including serum hormone measurements are not always comparable, several independent prospective studies have reported evidence supporting an association between circulating estrogen levels and breast cancer risk. Further, it is believed that relatively small individual differences in serum hormone levels (20 ) can multiply lifetime risk for a particular cancer by two- to threefold. For cancers other than breast and uterine,...

AReductases

Molecular cloning studies have revealed the existence of two genes that encode isoenzymes of 5a-reductases. The isoenzymes are designated types 1 and 2 and have distinct biochemical properties and tissue distributions. They are encoded by the SRD5A1 and SRD5A2 genes, respectively. The type 1 isoenzyme is found primarily in the liver and skin. It is optimally active at an alkaline pH. In contrast, the type 2 isoenzyme predominates in urogenital tissues and is optically active at an acidic pH. The SRD5A2 gene is located on chromosome 2 (2p23)90 and spans over 40 kb of genomic DNA, with five exons and four introns.91 The type 2 isoenzyme plays a major role in prostate development and disease and is highly sensitive to inhibition by finasteride. The therapeutic benefit of finasteride in the treatment of benign prostatic hyperplasia is due to its inhibitory effect on the type 2 isoenzyme, which predominates in the prostate.

Phytoestrogens

Dietary phytoestrogens, plant substances that are structurally or functionally similar to estrogen, have been proposed to act as estrogen antagonists in breast, prostate, and endometrial cells. However, epidemiological studies of dietary phytoestrogens and breast cancer have been inconclusive. Some studies indicate that soy intake may reduce a woman's risk of premenopausal breast cancer 77-79 however, at least one study found no association between dietary soy and breast cancer.80 One study has also reported a decrease in risk for postmenopausal breast cancer.79 Ingram et al.81 re-examined the association between phytoestrogens and breast cancer by measuring urinary excretion rates of two classes of phytochemicals and found that an inverse relationship exists with the risk of both pre and postmenopausal breast cancer and urinary excretion. It remains untested whether the measured phytochemicals actually serve as markers of other correlated dietary components, such as fiber, which also...

Raceethnicity

Probably the most interesting epidemiological feature of prostate cancer is its rather enormous international, or more precisely racial ethnic, variation in incidence. It is among the most internationally variant of all cancers.3 African-American men have the highest rates of prostate cancer in the world, exceeding the rate of any other racial ethnic group and any other countrywide incidence by almost twofold. Although there has been speculation that black Africans also have high rates of prostate cancer, convincing data are currently lacking, due to an absence of comprehensive cancer registries in black African countries and to the relatively short average life span still sustained by most African men. Such data would prove most useful in helping resolve whether the high risk in African Americans is largely due to genetic predisposition, lifestyle characteristics, or a combination of these factors. Asian men indigenous to China, Japan, and Korea and probably other countries as well...

Family Risk

Other than age and race ethnicity, the only firmly established risk factor for prostate cancer is family history. Men with a first-degree relative (father, sibling) with a history of prostate cancer have roughly two to three times the risk of prostate cancer compared to men with no such history. Risk is increasingly elevated as the number of first-degree relatives with prostate cancer increases men with three or more such first-degree relatives have an 11-fold increase in risk over men with no such history.5 Although there have been surprisingly few studies of this relationship, having such a relative with prostate cancer at a young age (< 65) conveys a higher risk than if such relatives develop prostate cancer at a later age. Although having either a brother or a father with prostate cancer conveys higher risk than having no relative with the disease, several studies have shown that the level of risk so conveyed is not comparable. Risk tends to be higher with a brother with...

The Future

The immediate future of molecular epidemiology will undoubtedly center around four main areas. Despite the limited reproducibility of loci identified to date as candidates for single-locus, high-penetrance susceptibility genes for prostate cancer, we can expect continued linkage analyses, identification of additional candidate loci, and undoubtedly the eventual identification and cloning of one or more of these genes. volving an increasing number of polymorphic variants, and will utilize high-throughput technology for large-scale analyses. Laboratory technology is moving toward utilization of haplotypes (multiple linked SNPs) to characterize genetic variants. Whether haplotype strategies will prove more useful than association studies involving multiple functional alleles to determine poly-genic models remains to be seen. As phenotype is ultimately of greater interest than genotype, the molecular epidemiology of prostate cancer will likely turn increasingly to proteomics as this field...

HSD3B1 and HSD3B2

The enzyme 3 -hydroxysteroid dehydrogen-ase is a critical component of the androgen-me-tabolism pathway because it catalyzes andros-tendione production in steroidogenic tissues and converts active DHT into inactive metabolites in steroid target tissues. The HSD3B gene family has two genes and five pseudogenes, all of which map to chromosome 1p13.92-94 The HSD3B1 gene encodes the type I enzyme, which is exclusively expressed in the placenta and peripheral tissues, such as prostate, breast, and skin. The HSD3B2 gene encodes the type II enzyme, which is predominantly expressed in classical steroidogenic tissues, namely, the adrenals, testis, and ovary.93,95-98 A number of mutations in HSD3B2 have been found to cause congenital adrenal hyperplasia, a rare mendelian disease manifested by salt wasting and incomplete mas-culinization in males.99 portant role in prostate cancer susceptibility. In a chromosomewide linkage study to evaluate different prostate cancer susceptibility loci on...

Conclusion

The role of androgens in normal prostate physiology is undisputed, and androgen blockade has been, and remains, one of the most widespread treatment strategies for advanced prostate cancer. Accordingly, a complete understanding of the role of androgens in prostate cancer has been pursued for quite some time. Based on new evidence that several genes in the androgen pathway, in addition to their roles in sporadic prostate cancer, may be involved in the etiology of HPC, further studies are warranted. By accessing candidate genes in the androgen-metab-olism pathway from multiple angles, the collective knowledge gained may allow for not only better family risk assessment, which has been a direct focus of the HPC studies, but also improved screening for prostate cancer, which has been a target of many population-based studies. Improved use of existing hormonal therapies and the development of designer therapies are promising goals of all efforts to understand the role of the androgen-action...

Growth Factors

There is growing evidence that activation of AR through these receptor tyrosine kinase pathways may play a functional role in human prostate cancer. Constitutive activation of EGFR has been seen with the expression of a mutant receptor, EGFRVIII, which lacks much of its extracellular domain. This mutant is amplified in glioblastomas.48 In prostate cancer, one group has reported increased protein expression of EGFRVIII in a large fraction of advanced-stage disease, but confirmatory studies are needed.49 Serum IGF-I levels are increased in prostate cancer and have been correlated with more aggressive tumors.50,51 However, unlike EGFR, no somatic mutations or amplifications of this growth factor gene and its receptor have been reported in prostate cancer. The receptor for IGF (IGF-R) signals through the phosphoinosi-tide 3-kinase (PI3K) pathway (see below, P13K-AKT Pathway), a parallel pathway to the Erk signal-transduction cascade, with ample opportunities for crosstalk along the way....

Coactivators

Or multiple copies of the a-helical LXXLL signature motif (where L is leucine and X is any amino acid). This motif mediates ligand-dependent coactivator NR or coactivator-coac-tivator interactions. Examples of coactivators known to directly interact with NRs include steroid receptor coactivator-1 (SRC-1), tran-scriptional intermediary factor 2 (TIF2), and amplified in breast cancer-1 (AIB-1). The latter is amplified in breast and ovarian cancers.81 Gregory et al.82 reported higher levels of AR, TIF2 and SRC-1 in recurrent human prostate cancer as well as in the CRW22 xenograft model. The AR-associated protein ARA70 is a prototype AR coactivator whose expression not only activates the transcription of androgen-responsive genes but also alters the ligand specificity of AR such that antagonists function as agonist.83

Modulating Apoptosis

Activation of pathways that inhibit apoptosis. Androgen-ablative therapy initially results in growth arrest, followed by proliferation, all while successfully evading apoptosis. Pathways that regulate apoptosis contribute to tumorigenesis and resistance to therapy. Bcl-2 is a potent modulator of the antiapoptotic pathway, which does not function through the AR pathway in prostate cancer cells. Bcl-2 is normally expressed in the basal cells of the prostate, which are resistant to the effects of androgen withdrawal. Basal cells are also thought to house the putative stem cells of the prostate (see below, Stem Cells). Bcl-2-negative secretory luminal cells undergo apoptosis in response to androgen deprivation. High levels of bcl-2 protein expression (as measured by immunohistochemistry) are seen with greater frequency as prostate cancers progress from localized (7 ) to AI tumors (67 ).86,87 Thus, it appears that bcl-2 enables prostate cancer cells to remain viable despite low levels of...

Stem Cells

We have alluded to the basal cell layer as the site of the putative stem cells of the prostate. These stem cells differentiate into secretory epithelial cells of the prostate. Basal cells do not express PSA and are dependent on androgen for survival but not growth.17 A pathognomic histo-logical feature of androgen-ablation therapy is basal cell hyperplasia.14 Under the selective pressure of androgen ablation, we may select for subsets of AI basal cells, which serve as seeds for tumor progression. Ablation of these cells may be a desirable therapeutic goal, but a better understanding of these cells is required. Studies have begun to identify candidate genes that define this stem cell population. Prostate stem cell antigen (PSCA) is one such candidate prostate stem cell gene.89 It shares 30 nucleotide homology with stem cell antigen 2, a member of the Thy-1 Ly-6 superfamily of glycosyl-phosphatidylinositol-anchored cell surface antigens. Interestingly, signaling through stem cell...

Summary

We have presented possible pathways that may lead to AI prostate cancer. An important factor in this progression involves the ability of prostate cancer cells to survive and grow in an androgen-depleted milieu. Cancer cells may gain this ability through alterations in AR function, which include amplification, mutations, and perturbations in signaling pathway components, which involve ligands, kinases, and coactivator-core- pressor complexes. Alternatively, parallel pathways not involving AR signaling may also contribute to progression. Due to the heterogeneity of prostate cancer, several pathways, acting singly or in concert, may ultimately lead to AI progression. We have highlighted the role of receptor tyrosine kinase signaling pathways since this is the arena in which many of the innovative clinical candidates are being developed, e.g., STI-571 and CCI-779, in addition to antitumor monoclonal antibodies, e.g., Trastuzumab and mAB-C225.96-98 The paradigm on which these agents have...

Clinical Biology

Normal prostate development and growth as well as the development of prostatic neoplasia are dependent on the action of the testicular an-drogens testosterone (T) and dihydrotestos-terone (DHT).2 Testosterone, secreted by the testicular Leydig cells, is taken up by a variety of tissues, including normal prostate and prostate cancer. The type II 5a-reductase enzyme acts within the prostate to metabolize T into the more potent androgen DHT.3 Dihy-drotestosterone and T form complexes with the androgen receptor (AR), which then interact with DNA via coactivator recruitment and RNA polymerase II to induce protein synthesis and cell replication. The major mechanism for reg The testes are not the only source of andro-gens, but they are responsible for 90 -95 of the circulating T present in healthy males. Adrenal androgens dihydro-epiandrostene-dione (DHEA) and androstenedione may be converted to T and DHT by hydroxysteroid de-hydrogenases. Adrenal androgens may also activate mutant ARs in...

Orchiectomy

Surgical castration, most commonly achieved with bilateral subcapsular orchiectomy, was one of the first forms of therapy available for prostate cancer. Its continued use in the twenty-first century identifies it as the clinical former standard against which newer hormonal therapies must be compared.23 Surgical castration results in a rapid fall in serum T concentration to 0 -10 Table 19.1 Hormonal Therapies of Proven or Potential Use in Prostate Cancer of its original level with a corresponding rise in serum LH levels. Around 80 of patients with advanced metastatic prostate cancer obtain improvement in clinical symptoms and extent of disease on imaging modalities as well as a fall in PSA in response to surgical castration. The mean duration of response to such hormonal manipulation is on the order of 12-18 months, after which the cancer progresses in a manner that is often resistant to further hormonal therapy as well as most other treatments.

Agonists

The first LH-suppressive agents in broad clinical use were LHRH agonists (leuprolide,25 goserelin acetate,12 buserelin26). They are the preferred form of hormonal therapy for prostate cancer in developed countries, despite being more expensive than surgical orchiectomy.27-29 Agonists of LHRH suppress both serum LH and T concentrations by 3-4 weeks after commencement.26,30,31 Prior to this, there is a transient increase in serum LH and T concentrations in the first few days that correlates with early response to increased LHRH effect on the HPG axis before the suppressive effect on LH secretion intervenes.32 This is of clinical importance because patients may experience a flare in disease activity in the first few days of therapy with the potential result of increased bone pain, urinary tract obstruction, and or spinal cord compression before disease regression occurs.14,33 In practice, the best way to avoid this is with administration of a peripheral AR blocker for several days prior...

Antagonists

Several LHRH antagonists (aborelix,39,40 cetrorelix41) have been developed and are now in trials for a variety of indications, including prostate cancer. These trials show that antagonists produce earlier castrate levels of T than LHRH agonists and are not associated with an early surge in serum T concentrations.40,42 The available preparations of LHRH antagonists require monthly injection, but depot formulation development to allow a longer interdose interval is under way. The role of LHRH antagonists in the treatment of prostate cancer remains to be determined, but they may provide an alternative to combined androgen blockade (CAB) when rapid castrate levels of T are required, such as in patients with spinal cord compression, bone pain, and or potential for bladder outlet obstruction. Delineation of the role of LHRH antagonists as acceptable alternatives to castration and CAB will require carefully designed randomized, stratified studies that evaluate long-term efficacy, side...