Endogenous Hormone Levels And Mammographic Density

The data listed above suggest that endogenous hormones are important determinants of mam-mographic density. However, to what extent nor mal variations in hormone levels in pre-menopausal women predict mammographic density levels is largely unknown. One study suggests that plasma levels of estrogen were the same but progesterone was 30 and 50 higher in women with the high-risk P2 or DY Wolfe pattern than in women with the lower risk N1 or N2 pattern.38 Women who were moderately physically active...

Other Candidate Genes

Work is emerging on other candidate genes that may fit into this model. Carrying high-risk alle-les of CYP17 and HSD17B1 together increased breast cancer risk among 850 incident cases and 1508 controls.119 The HSD17B1 gene encodes the 17HSD type 1 enzyme, which catalyzes the final step of E2 biosynthesis, namely, the conversion of estrone to the more biologically active E2. Type 1 is expressed in both normal and malignant breast epithelium.138 Several polymorphisms have been identified in...

T187m R227q F234l F194l

Peat polymorphism in the 3'-untranslated region. Constitutional DNA missense substitutions are identified below the gene in the single-letter amino acid code. 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...

References

Pike MC, Ross RK, Lobo RA, Key RJA, Potts M, Henderson BE. LHRH agonists and the prevention of breast and ovarian cancer. Br J Cancer 60 142-148, 1980. 2. Trichopoulos D, MacMahon B, Cole P. Menopause and breast cancer risk. J Natl Cancer Inst 48 605-613, 1972. 3. Feinleib M. Breast cancer and artificial menopause a cohort study. J Natl Cancer Inst 41 315-329, 1968. 4. Hirayama T, Wynder EL. A study of the epidemiology of cancer of the breast II. The influence of hysterectomy. Cancer 15 28-38,...

Reproductive Factors

It has been consistently shown in the general population that early age at first pregnancy and an increase in parity are associated with a reduction in the incidence of breast cancer.48,49 In addition, multiparity is protective against ovarian cancer.50 However, several studies of women at high risk because of a family history have produced conflicting results. Colditz et al.51 showed an adverse effect of early first pregnancy on breast cancer risk, whereas other studies have shown no...

Antiandrogens

In the setting of metastatic prostate cancer, peripheral androgen blockers as monotherapy are traditionally considered inferior to estrogens,43 castration, or CAB.44 However, such monother-apy may be associated with early preservation of sexual function compared to CAB (see below, Combined Androgen Ablation).45,46 Some patients with prostate cancer who develop disease progression as determined by increasing symptoms, increase in tumor volume, and or increase in serum PSA while on antian- drogen...

Dietary Fat and Fiber

Much attention has been focused on dietary differences, particularly in fat consumption, to ex plain both the international pattern of breast cancer occurrence and changes in rates of breast cancer following migration to high-risk countries from low-risk countries.66,67 International breast cancer mortality rates correlate highly with per capita consumption of fat in the diet (correlation coefficient r 0.93).67 When international breast cancer incidence rates rather than mortality rates are...

Info

Lefebvre A, Chen I, Desreumaux P, et al. Activation of the peroxisome proliferator-activated receptor g promotes the development of colon tumors in C57BL 6J-APC Min + mice. Nature Med 4 1053-1057, 1998. 409a. Sarraf P, Mueller E, Jones D, et al. Differentiation and reversal of malignant changes in colon caner through PPARg. Nature Med 4 1046-1052, 1998. 410. Lim H, Gupta RA, Ma WG, et al. Cyclo-oxyge-nase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes...

Smoking And Alcohol

Smoking has not been found to be a risk factor for breast cancer in the general population.36 However, smoking was found to be protective against breast cancer in BRCA1 2 carriers in one study.37 The reduction in breast cancer incidence was significant for BRCA1 carriers who had smoked 4 or more pack-years (odds ratio 0.47, 95 confidence interval 0.26-0.86). The reduction in BRCA2 carriers was greater (0.39) but did not reach statistical significance, possibly because of small sample size. The...

The Chromatin Link

Eukaryotic DNA is highly organized into a higher-order structure termed chromatin, with repeats of a protein-DNA complex that consists of a histone octamer (nucleosome) wrapped by 146 base pairs of DNA. Acetylation of histones H3 and H4 is thought to generate an open chro-matin conformation, which allows access of the transcriptional apparatus to the regulatory or promoter regions of genes. As such, hyper-acetylated chromatin is often associated with transcriptionally active genes, while...

Summary

Highly predisposing mutations in known genes such as BRCA1, BRCA2, and possibly chk2 and ATM, account for only some 20 of the familial clustering of breast cancer, most of which probably has a genetic basis. The nature of the genes that may account for the remaining 80 is still unknown. It is likely (but not certain) that the spectrum of normal genetic variation in the population, rather than rare genetic mutations, plays a substantial part in determining risk. Model fitting suggests that an...

Association of 16aHydroxylated Estrogens with Breast Cancer Risk

On the basis of their in vivo studies, Fishman and colleagues135 suggested that increased for Chemical rearrangement NMW rotein Chemical rearrangement NMW rotein Figure 2.6 Proposed mechanism for the formation of the stable adduct of 16a-hydroxyestrone with protein. mation of 16a-hydroxylated estrogen metabolites might be associated with increased risk of developing breast cancer. Their initial studies showed that 2- and 16-hydroxylation of estradiol was minimally affected by age and did not...

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...

Atypical Cofactors

Although originally identified as a ligand-de-pendent coactivator,212 RIP140 has unusual properties that suggest that it may modulate receptor function in a distinct manner from other co-activators and corepressors. For example, RIP140 (when overexpressed) strongly suppresses the transactivation activities of several NRs in the presence of their cognate ligands, including ER, RAR X, liver X receptor alpha (LXRa), and PPARy. Unlike the p160 family proteins, which contain three LXXLL motifs...

Retinoid X Receptors

As common heterodimerization partners for members of the class II NRs, RXR activity is involved in nearly all nonsteroid NR-dependent signaling pathways (Table 3.6, Fig. 3.4). Its involvement in RAR, VDR, TR, and orphan receptor physiology is well documented RXR het-erodimerization is required for the activity of at least 11 disinct receptor pathways.51,373 Despite expression of at least one RXR isoform in every tissue, null mutation of RXRa is embryonic lethal at embryonic day (E) 10.5 to...

Pxrsxr

The PPAR, LXR and FXR receptors are apparently activated by metabolites of fatty acids, oxysterols, and bile acids, respectively, suggesting that they function as homeostatic sensors within these metabolic pathways. For PPARa, activity is influenced by xenobiotic compounds as well as putative endogenous fatty acids, suggesting that this receptor may be involved in P-450 induction in response to dietary or environmental toxins. Another class of orphans that exhibits liver-specific expression and...

Recruitment of Cofactors

The DNA-bound AR dimer recruits a multiprotein complex containing members of the basal transcription machinery (e.g., TFIIF) and additional essential proteins, termed cofactors, which upregulate (coactivators) or inhibit (corepres-sors) target gene expression.53 The p160 family of coactivators, consisting of three related proteins, steroid receptor coactivator-1 (SRC-1), glucocorticoid receptor interacting protein-1 (GRIP1) and amplified in breast cancer-1 (AIB1) are the best-characterized of...

Isabell A Schmitt Milana Dolezal Michael F Press

Breast cancer is the most common malignancy in women, and treatment is challenging. The potential role of hormonal therapy in breast cancer treatment was first demonstrated by George Beatson more than 100 years ago, when he showed that two of three premenopausal women with metastatic breast cancer responded to ovarian ablation.1 Subsequently, Huggins and Bergenstal2 demonstrated that postmenopausal women with metastatic breast cancer responded to ovariectomy and adrenalectomy. Despite the...

Contents

Introduction and Background 1 Brian E. Henderson and Roberta McKean-Cowdin 2. Biosynthesis, Transport, and Metabolism of Steroid Hormones 12 Frank Z. Stanczyk and Philip Bretsky 3. The Nuclear Receptor Superfamily 38 John M. Rosenfeld, Hung-ying Kao, and Ronald M. Evans 4. Genomic Approaches to the Genetics of Hormone-Responsive Cancer 99 Joel N. Hirschhorn, Celeste Leigh Pearce, and David Altshuler 5. Breast Cancer Epidemiology and Molecular Endocrinology 120 Heather Spencer Feigelson 6. The...

Family History and Inherited Susceptibility

As detailed in chapter 7, family history of breast cancer is associated with increased risk. This is especially so if the history includes a first-degree family member who was affected at an early age or had bilateral disease. Much attention is given to hereditary breast cancer when, in fact, those cases that can be attributed to a single-gene mutation are very rare. Epidemiological evidence suggests that BRCA1 and BRCA2 together account for only about 5 of all breast cancers.110 Germline p53...

Hormone Response Elements and the DNABinding Domain

The concept that hormone NRs function as sequence-specific DNA-binding transcription factors was substantiated when a hormone response element (HRE) for the GR was first identified by mutational analysis of the hormone-responsive long terminal repeat (LTR) of the mouse mammary tumor virus (MMTV) (Fig. 3.3).24 Since the establishment of this concept, the DBD has been an area of intense investigation to determine how specific recognition of its HRE target are conferred. The DBD is comprised of...

Expression in Adipose Tissue

Aromatase is expressed in the undifferentiated stromal mesenchymal cells of adipose tissue (preadipocytes) and not in the mature lipid-laden adipocytes.41 Under normal circumstances, adipose stromal cells contain CYP19 transcripts derived primarily from promoter I.4. This TATA-less promoter is stimulated by class 1 cytokines e.g., oncostatin M and interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a). In addition, activity of promoter I.4 has an obligate requirement for glucocorticoids.42...

Amino Terminal Transactivation Domain

The large NTD of the AR is unique among NRs in that it is responsible for almost the entire transactivation potential of the protein. It contains at least three overlapping constitutive transactivation domains, which, in the context of the full-length receptor, are activated or inhibited by conformational changes resulting from hormone binding at the LBD or by other mechanisms. In particular, two activation functions, AF-1 (aa 51-210) and AF-5 (aa 369-492), which contain LxxLL-like motifs,...

Comparison of Risks According to Type of Postmenopausal Hormone Therapy Used

In the collaborative reanalysis, information on the constituents of preparations used most was available for just under one-half of the eligible women. The vast majority of these women had used estrogen-only therapy (80 ) with only 12 reporting having mostly used preparations containing both estrogen and progestagen. When the effects of recency and duration of use were examined separately within these data for preparations containing estrogen alone, preparations containing progestagen (with or...

C

Treatment discontinuations, less erectile dysfunction, and better QOL than the goserelin plus flutamide arm. While this study might be interpreted as favoring use of high-dose biclutamide over CAB, there are some concerns related to the conduct, analysis, and interpretation of the data. Potentially significant differences in pre-treatment features such as baseline PSA and tumor grade are not addressed and make efficacy data difficult to evaluate. The trial mixed stage C and D patients and...

Antitumor Actions

Raloxifene inhibits the growth of DMBA-induced rat mammary carcinoma180 and, more importantly for the proposed evaluation as a preventive, reduces the incidence of N-nitrosomethylurea-induced tumors if given after the carcinogen but before the appearance of palpable tumors17,181 (Fig. 12.10). As would be anticipated with a drug that has a short biological half-life, raloxifene is not superior to tamoxifen at equivalent doses. There is no doubt that ralox-ifene and its analogues are effective...

Tamoxifen

Tamoxifen is widely used in the treatment of breast cancer. Although the exact mechanisms for its effect are not known, it has also been found to protect against breast cancer.29 As such, one would expect tamoxifen to result in reduced mammographic density and increased sensitivity of the mammograms. In a pilot study of 19 premenopausal women, tamoxifen was associated with a substantial reduction in density.30 Similarly, a change in Wolfe's parenchymal pattern to more lucid patterns was...

Biological Basis For Raloxifene As A Breast Cancer Preventive

Raloxifene, originally named keoxifene or LY156758,170 was discovered in the breast cancer program at the laboratories of Eli Lilly (Indianapolis, IN). The drug has a high binding affinity for the ER,171,172 primarily because it has strategically located phenolic groups (Fig. 12.1). Raloxifene and an analogue, LY117018,59,173-175 are short-acting compounds with poor bioavailability due to rapid phase II metabolism.176 Indeed, a concern in the early clinical trials was an inability to monitor...

Evidence For Testing Tamoxifen As A Chemopreventive

The 1998, Oxford overview analysis47 combined 55 randomized trials that began before 1990, comparing adjuvant tamoxifen therapy to no ta-moxifen prior to recurrence. The study population of 37,000 women with node-positive and node-negative breast cancer comprised 87 of the known, randomized clinical trials with tamoxifen. Of these women, fewer than 8000 had a very low or zero level of ER and 18,000 were classified as ER-positive. The ER status of the remaining nearly 12,000 women was unknown....

Genetic Testing For Brca12 Mutations

The first step in genetic testing for BRCA1 2 is to identify a mutation in an affected family member. Mutations are widespread throughout the gene, and many are novel, i.e., specific to a family. It is important to establish that a mutation is definitely the cause of the disease in the family mutation testing is then offered to unaffected relatives for the specific mutation previously found in their affected relative. This is accompanied by full counseling, which usually consists of at least...

HolohPPAFfySRCI HolohERa BRL496534HT

Figure 3.6 Activation function 2 (AF-2) forms a favorable interaction with the nuclear receptor (NR) box only in the presence of receptor agonists. Comparison of the holo human peroxisome proliferator-activated receptor gamma (hPPARy) human steroid receptor coactivator 1 (hSRCl) cocrystal and antagonist-bound human estrogen receptor alpha (hERa) crystal structures. Schematic diagrams of the hPPARy ligand-binding domain (LBD) complexed with the synthetic agonist BRL49653 (Rosiglitazone) and the...

Colin D Clyne Evan R Simpson

Recent models of estrogen insufficiency have challenged traditional concepts of estrogen ac-tion.1-3 Studies of humans with natural mutations in the genes that encode the estrogen re-ceptor4 or cytochrome P-450 aromatase5 and of estrogen receptor and aromatase knockout mouse models6-11 have revealed hitherto unexpected roles for estrogen in both males and females. For example, the critical role of estrogen in the spermatogenic process12 suggests that this hormone might more appropriately be...

Dax1 Shp1

Viable, agressive, defective limbic system, blindness accumulation, loss of protection against dietary bile acids Mutation in enhanced S cone syndrome, visual impairment Loss of function mutations, X-linked hypogonadism Phenotypes of homozygous null mutations of the indicated mouse receptor genes are summarized where available, as are expression patterns for individual receptor genes. NGFI-B, nerve growth factor induced receptor B Nurr1, Nur related receptor 1 NOR, neuron derived orphan...

Crosstalk Between Nuclear Receptors and Other Transcription Factors

Nuclear receptors can also influence the activities of other transcription factors in either a positive or a negative manner (Fig. 3.11). In some contexts, this crosstalk does not require the DBD. The best-characterized examples of NR crosstalk are between GR and AP-1 and between GR and NF-kB.252-255 The GR induces differentiation and represses the production of proinflammatory cytokines, while AP-1 promotes proliferation and inflammatory responses.256-258 The latter is a sequence-specific...

Regulation

Sex hormone-binding globulin is regulated in a complex fashion, which is poorly understood. Originally, it was thought that the major regulators of SHBG biosynthesis were estrogens and androgens. This hypothesis was based on the observation that normal women have significantly higher serum SHBG levels than normal men. However, subsequently, a number of studies showed that estrogens and androgens do not always account for the significant changes in circulating SHBG levels observed in clinical...

Molecular Biology of Estrogen Receptors a and p

Expression cloning of the human ER using monoclonal ER antibodies provided the first full-length sequence of ERa.32,33 In common with the other members of the steroid thyroid hormone receptor family of nuclear receptors, ERa has six main structural and functional domains (A-F) a variable or regulatory domain containing a transcriptional activation function (A B), a DNA-binding domain (C), a hinge region (D), a ligand-binding domain (E), and a region that plays a role in distinguishing agonists...

Bruce Ponder

Breast cancer, like most common cancers, tends to cluster in families.1 There is evidence, discussed below, that most of the family clustering results from inheritance rather than shared environment. If we knew the genes that underlie the family clustering, the knowledge might be applied in several ways 1. Understanding of cancer development application to treatment and prevention. The genes can be thought of either as part of the sequence of events that must be accumulated to turn a normal...

Brian E Henderson Roberta Mckeancowdin

The concept that hormones are an important part of the carcinogenic process, at least in some organs, was initiated over 100 years ago by the observations of Beatson1 on the relationship between cancer of the breast and ovarian function. Subsequent experimental studies in rodents by Bittner2,3 demonstrated that hormones could increase the risk of mammary cancer. In parallel, Rous and Kidd4 and later Berenblum5 popularized the multistage concept of carcinogenesis. Elegant studies of the...

Hellevi Peltoketo Veli Isomaa Debashis Ghosh Pirkko Vihko

Oophorectomy in a woman's early adult years substantially lowers her risk of breast cancer.1-4 This is an example of the abundant epidemio-logical and endocrine data which indicate that estrogens are involved in sporadic breast cancer and promote growth.5-8 Oophorectomy also reduces the risk of breast cancer among BRCA1 mutation carriers,9 which hints at the general role of estrogens in the proliferation of breast epithelial cells. Due to the striking effect of ovariectomy, it is assumed that...

New Agents

Newer SERMs with slight modifications of chemical structure are being studied with the goal of increasing the spectrum of antitumor activity and reducing toxicity (Fig. 12.11). The ongoing investigation of several molecules may demonstrate applications as breast cancer and or osteoporosis treatments. Most importantly, the drugs may be multifunctional medicines useful for the prevention of osteoporosis, coronary heart disease, and breast cancer. The ideal agent would (1) not produce premature...

Prevention Of Breast Cancer With Tamoxifen

In 1986, Cuzick et al.156 outlined a prevention trial with tamoxifen in women at high risk of breast cancer. The previous year, Cuzick and Baum157 documented a marginally significant reduction in the risk of a second primary cancer in the contralateral breast of breast cancer patients after 2 years of tamoxifen. This initial observation was confirmed in larger randomized clinical trials. Fornander et al.158 recruited 1846 postmenopausal patients for the Stockholm Adjuvant Tamoxifen Trial and...

Implications For Women With Family History

Sensitivity of mammography may be substantially lower in women with than without a family history of breast cancer. Further, sensitivity has been found to drop faster as the screening interval increased from 7 to 13 months in women with a family history (78.6 to 68.8 ) compared to all women under age 50 (87.5 to 83.6 ).11 This suggests that these women are more likely to have fast-growing tumors. Whether hormonal manipulation is more or less likely to result in density changes in these women is...

Parity

Early age at first birth (i.e., before age 20) reduces the risk of breast cancer by about 50 relative to nulliparous women. Full-term pregnancies at later ages add smaller increments of protection, and women who have a first pregnancy over the age of 30 are actually at higher risk of breast cancer than nulliparous women.24 This paradoxical effect of a later first full-term pregnancy has been repeatedly confirmed in epi-demiological studies. Furthermore, a recent full-term pregnancy also...

Concluding Remarks

The primary risk factors for breast cancer stem from prolonged endogenous and exogenous hormonal exposures. However, the genetic basis of endogenous hormone levels as an important risk factor for breast cancer has been recognized only recently. Long thought to be largely an environmentally caused cancer, it is now increasingly obvious that genetic susceptibility, through germline polymorphisms in metabolic genes, plays a critical role. Certainly the complete multigenic model of breast cancer...

Giske Ursin

In the past few decades, much interest and controversy have surrounded the question of who will benefit from regular mammographic screening. A number of studies have been conducted, including several randomized trials.1,2 Although some issues have been resolved, many remain. Mammographic screening overall appears to be associated with reduced mortality from breast cancer. However, it is not clear at what age the benefit begins and at what age the cost-benefit effect becomes reasonable. The...

Role Of Mammographic Density

Mammographic sensitivity is lower in women with mammographically dense breasts.11,12 The differences in sensitivity and false-positive rate observed in women below and above age 50 parallel the decrease in mammographic density observed with increasing age between 35 and 55.14,15 Very dense mammographic patterns especially appear to change to lower-risk patterns during the perimenopausal period (age 45-55).14 There is, of course, no abrupt change in the positive predictive value of mammogram at...

Association Studies From Genotype to Phenotype

Genetic association studies are simple in conception one or more putative causal variants are identified and their frequency is compared in populations with and without the trait of interest. In fact, all human genetic approaches conclude with an association study, for both simple and complex traits, whether guided by linkage analysis or a hypothesis about a candidate gene the association of genotype with phenotype indicts a gene as causing disease.70 Traditionally, however, the term genetic...

Lipids

Raloxifene produces a significant decrease in low-density lipoprotein cholesterol, but high-density lipoprotein cholesterol remains the same.194,196,197 Additionally, triglycerides do not rise during raloxifene treatment. Laboratory data on the rabbit strongly support that ralox-ifene prevents atherosclerosis 198 however, data from primates fed high-cholesterol diets do not confirm this.199 A prospective, randomized clinical trial is currently addressing the merit of raloxifene in the reduction...

Evidence For Inherited Predisposition To Breast Cancer

Familial Breast Cancer

The evidence comes from familial clustering. It is clearest in families such as that shown in Figure 7.1, where several individuals are affected in successive generations. Such a pattern can only be due to a highly penetrant, dominantly inherited predisposing mutation. The gene can be identified empirically using linkage analysis, followed by positional cloning indeed, two such genes have so far been identified, BRCA1 and BRCA23 Mutations in BRCA1 or BRCA2 account for the majority of families...

Peroxisome Proliferatoractivated Receptors And Cancer

The ability of PPARy to promote and establish differentiated phenotypes in at least two cell types (i.e., adipose and macrophage) suggests that PPARy activators may also be useful to block proliferation in malignant cells that express this receptor. In fact, preliminary studies demonstrate that in breast cancer and liposar-coma cell lines PPARy and or RXR ligands are capable of limiting cell growth by promoting dif-ferentiation.407,408 This differentiation therapy is similar in concept to RA...

Transfer of Cholesterol to the Mitochondrion

Steroid-synthesizing cells have at least three metabolically active pools of cholesterol (1) a small, metabolically active pool of free cholesterol (2) a large storage pool in which cholesterol is stored as cholesterol esters of free fatty acids and (3) a fixed pool of membrane cholesterol, which is not available for steroid synthe-sis.9 The free cholesterol pool is formed from endogenous conversion of acetate to cholesterol via a complex series of reactions and by hydrolysis of cholesterol...

Use of Any Type of Postmenopausal Hormone Therapy

Most studies of postmenopausal hormone therapy and breast cancer have found a small increase in the risk of breast cancer associated with ever use (Fig. 6.10), with an overall average risk of breast cancer in ever-users compared to never-users of 1.14 (95 CI 1.09-1.49). Further examination of breast cancer risk according to the pattern of use of postmenopausal hormone therapy shows that this excess risk is largely confined to current and recent users and among these women the risk increases...

Darcy V Spicer Malcolm C Pike

A potential role for analogues of gonadotropin hormone-releasing hormone (GnRH) to prevent cancers of the breast, ovary, and endometrium was first suggested by Pike et al.1 The rationale for considering GnRH analogues is their ability to suppress ovulation and sex-steroid production. The suppression of ovulation should prevent ovarian cancer, and the suppression of sex steroids should prevent cancers of the breast and endometrium. However, the GnRH analogue-induced hypo-estrogenic state will...

Expression in Breast Cancer

Estrogen levels are consistently elevated in breast tissue of cancer patients compared to normal individuals.53,54 The presence of a breast tumor enhances the local expression of aromatase three- to fourfold in the surrounding breast adipose tissue, to levels equivalent to those within the tumor itself. Furthermore, there is a gradient of aromatase expression with the tumor as its focus.55-57 Breast tumors produce factors that stimulate the proliferation of mesenchymal cells surrounding them,...

Background

Postmenopausal hormone therapy is taken here to refer to the use of preparations containing estrogen(s), with or without progestagen(s), around the time of the menopause, primarily for the relief of menopausal symptoms. Use of such therapy has increased dramatically in the last decade such that by 1998 around one-third of women aged 50-64 in England were estimated to be using it.13 In addition, recent estimates suggest that between 20 and 30 of women aged 45-64 in many developed countries,...

Orphan Nuclear Receptors Reverse Endocrinology And Pharmacology

As stated above, several NRs that were once considered orphans are now known to play important physiological and pathophysiological roles in response to xenobiotics, dietary and cellular metabolites, presumably as paracrine or in-tacrine mediators. Indeed, whole families of receptors have emerged that exhibit neural or steroidogenic expression patterns and likely govern various aspects of sexual development, hormonal regulation, or behavior. However, of the more than 60 NRs that have been...

Nuclear Receptor Corepressors

The notion that certain NRs can actively repress basal transcription was derived from the study of the oncogene v-erbA, encoded by avian erythroblastosis virus (AEV).165,166 This study demonstrated that, unlike its cellular counterpart TRa, v-erbA encodes a constitutive tran-scriptional repressor due to loss of ligand-bind-ing activity. It was later shown that this silencing effect by receptors is mediated by cofactors. Four mammalian NR co-repressors have been isolated, including the small...

Estrogen Receptor Status

Figure 12.9 Incidence of osteoporotic fractures of the hip, wrist, and spine observed in the placebo- and ta-moxifen-treated arms of the National Surgical Adjuvant Breast and Bowel Project tamoxifen prevention trial P-1. (Adapted from Fisher et al.106) Figure 12.9 Incidence of osteoporotic fractures of the hip, wrist, and spine observed in the placebo- and ta-moxifen-treated arms of the National Surgical Adjuvant Breast and Bowel Project tamoxifen prevention trial P-1. (Adapted from Fisher et...

Joel N Hirschhorn Celeste Leigh Pearce David Altshuler

Over the last 20 years, there has been remarkable progress in our understanding of the molecular basis of cellular function and disease, particularly within the area of cancer biology.1-3 Despite this rich understanding of fundamental biological mechanisms, however, we remain surprisingly ignorant of the specific molecular defects responsible for risk and progression of disease. To the extent that we can uncover why one person is predisposed to cancer and another less or why one tumor displays...

Sex Steroid Hormone Receptors and Cancer

Because of their involvement in the regulation of growth control and differentiation during development of the reproductive system, ER, PR, and AR activities are targets of therapeutic intervention in cancers associated with these tissues. Both ER and PR are expressed in breast and uterine cancers, and activation of AR has been implicated in prostatic cancer.306,307 Onco-genes such as c-myc, c-fos, and c-jun are both direct and indirect transcriptional targets for these receptors in these...

Lacassagnes Prevention Principle A Target And An Estrogen Antagonist

In 1962, Jensen and Jacobson9 demonstrated that 3H -estradiol bound to and was retained by estrogen target tissue, e.g., uterus, vagina, and pituitary gland, in the immature female rat. They proposed that an ER must be present in these tissues to capture circulating steroids and initiate the cascade of biochemical events. Toft and colleagues23,24 first identified the ER as an ex-tractable protein from rat uterus. Subsequently, Gorski et al.25 and Jensen et al.26 independently proposed...

Nuclear Receptor Coactivators

Transcriptional activation by NRs is a complex process as NR ligand-dependent activation is thought to require the assembly of a multi-component complex containing an array of co-activator proteins, many of which possess intrinsic enzymatic activity, as well as a variety of interaction motifs. Sequence analyses of receptor-interacting protein 140 (RIP140) and p160 family proteins identified multiple copies of a conserved motif, LXXLL (where L is leucine and X can be any amino acid), termed the...

Conclusions

It is clear from this review that hormonal contraceptives, postmenopausal hormone therapy, and DES are associated with an increase in breast cancer risk. In contrast, results with respect to fertility-enhancing drugs, although broadly reassuring, must still be viewed as equiv ocal. In terms of future research, the most urgent questions concern hormonal contraceptives and postmenopausal hormone therapy since these preparations are currently used by substantial numbers of women throughout the...

Expression in Ovary

Aromatase is expressed in the preovulatory follicles and corpora lutea of premenopausal women. Expression in granulosa cells is regulated by follicle-stimulating hormone (FSH), which increases intracellular cyclic adenosine monophosphate (cAMP) through activation of adenylyl cyclase.36 Two distinct elements within promoter II mediate the FSH-induced cAMP signal (Fig. 8.3). The first element, located at position 211 202 (TGCACGTCA), resembles the consensus palindromic cAMP response element...

Other Orphan Receptors

Preliminary analysis of the activities and expression patterns of members of the large family of orphan receptors suggests that many are involved in the regulation of liver-specific metabolism (i.e., HNF-4, PPARa, LXR, FXR, LRH-1, SHP-1, SXR, CAR), while others seem to play roles in steroidogenesis, sexual differentiation, and germ cell development (i.e., TR2, TR4, SF-1, GCNF, NGFI-B, DAX-1) or neural function and specification (ERR, ROR, TLX, photoreceptor nuclear receptor PNR ) (Tables 3.8,...

Gonadotropinhormonereleasing Hormone Analogues

In women, GnRH analogues induce reversible inhibition of ovarian function and steroid pro duction. Native GnRH produced by the hypothalamus controls the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary and, thence, gonadal steroid hormone production. Inhibition of GnRH action can be achieved either with recently introduced antagonists or with agonists that desensitize GnRH receptors. Potent synthetic agonists of GnRH administered to pre-menopausal...

Orphan Nuclear Receptors

Steroid and thyroid receptors were originally identified as purified proteins that were capable of binding to radiolabeled hormone ligands. With the advent of molecular cloning, cDNAs encoding novel families of receptors were isolated by virtue of homology similarity within the DBD or by interaction screens utilizing RXRs. Many of these receptors have no known ligand and, therefore, represent orphan NRs that participate in as yet unidentified signaling pathways. For a few of these receptors,...

Biological Basis For Tamoxifen As A Breast Cancer Preventive

Tamoxifen was selected for testing as a preventive based on (1) animal studies that demonstrated it could prevent carcinogenesis,49-52,103 (2) extensive clinical experience that showed few serious side effects, and (3) a beneficial profile of estrogen-like action in maintaining bone density and reducing circulating cholesterol. Ta-moxifen was already known to reduce the incidence of contralateral breast cancer47 and to have a favorable toxicity profile, making the drug the primary agent to test...

Combined Oral Contraceptives

Almost all studies of combined oral contraceptives and breast cancer have published results on the risk of breast cancer associated with ever use of such contraceptives. Overall it appears that women who have used combined oral contraceptives are at a very slightly increased risk of breast cancer relative risk (RR) 1.07, 95 confidence interval (CI) 1.03-1.10 , although estimates from individual studies are by no means consistent (Fig. 6.1). This is perhaps not surprising since ever use is a...

Fertility Enhancing Drugs

Women who undergo treatment for infertility can be exposed to a variety of hormonally active drugs, including clomiphene citrate, human menopausal gonadotrophin, and gonadotrophin-releasing hormone. Studies examining the relationship between use of fertility drugs and breast cancer risk have been hampered by small numbers of women and the inability to adequately control for all important confounding factors. Bearing this in mind, their findings have been generally reassuring, showing no...

Gillian K Reeves Emily Banks Timothy Ja

The importance of endogenous hormones in the etiology of breast cancer is evident from the strong relationships between breast cancer risk and certain aspects of a woman's reproductive history, such as age at menarche, age at first birth, and age at menopause.1 More recently, the risk of developing breast cancer among post-menopausal women has also been shown to increase substantially with increasing levels of circulating estradiol,2 thus providing more direct evidence for the role of hormones...

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...

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...

Atomic Structure of the Nuclear Receptor Ligand Binding Domain

Receptor-hormone interactions were initially explored using genetic and biochemical techniques to assess the consequences of radiolabeled ligand binding to classical hormone receptor LBDs. The identification of whole new families of orphan nuclear receptors, however, accelerated the quest to obtain X-ray crystallo-graphic and nuclear magnetic resonance spec-troscopic structural models of both apo and holo LBDs. Similarly, the identification of ligands that antagonized the transcriptional...

Lactation

Lactation has been increasingly reported to provide protection against breast cancer development. If the cumulative number of ovulatory cycles is directly related to breast cancer risk, a beneficial effect of long duration of nursing would be expected since nursing results in a delay in re-establishing ovulation following a completed pregnancy. With only a small proportion of mothers having a large number of cumulative nursing months, most epidemiological studies have been unable to provide...

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...

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...

Anthropometric Factors

Height, weight, body mass (measured most commonly by body mass index, or BMI), fat distribution patterns, and weight change have been shown to influence breast cancer risk. The data on breast cancer risk and height have been relatively consistent in demonstrating an increase in risk with increased adult height. A pooled analysis of seven prospective cohort studies of height and breast cancer risk reported relative risks for breast cancer, after adjusting for other risk factors, of 1.02 per 5 cm...

Multigenic Models Of Susceptibility

Although there is evidence that hormonal secretion and metabolism can be environmentally influenced, e.g., through diet and physical activity, the control of hormonal patterns is largely genetically regulated. It has been hypothesized that a multigenic model of breast cancer predisposition can be developed that includes polymorphisms in genes involved in estrogen biosynthesis and intracellular binding.118 This model would include functionally relevant polymorphisms that would act together and...

How Ovarian Steroids Affect Mammographic Density

The association between ovarian steroids and mammographic density parallels what is known about the effects of ovarian steroids and breast cell proliferation.43 Breast cell proliferation is higher in pre- than postmenopausal women and higher in women in the luteal than in the follicular phase of the menstrual cycle. In short, high estrogen progesterone levels are associated with high amounts of breast cell proliferation. A number of studies have examined what his-tological components are...

Nuclear Receptor Ligands

Consideration of the diverse stereospecific structures of the known ligands for NRs reflects the diversity and size of the superfamily (Figs. 3.8-3.10). As discussed previously, the ligand-binding function of NRs evidently evolved in very small steps, yielding a large family of proteins capable of discriminating minor differences in chemical structures. The majority of known ligands are lipophilic, polycyclic planar compounds containing a variable number of ring structures, side chains, and...

Ligand Entry Loop Interactions

The open and closed conformations of the substrate-entry loop are shown in Figure 9.4, where the backbones of the apo- and holoenzyme Figure 9.3 (a) Schematic diagram of the active site of the 17 -hydroxysteroid dehydrogenase 1 (17HSD1)-equilin-oxidized nicotinamide adenine dinucleotide phosphate (NADP+) ternary complex. Residues belonging to the hydrophilic catalytic and recognition ends, as well as residues lining the hy- Figure 9.3 (a) Schematic diagram of the active site of the 17...

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...

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...

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...

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...

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...

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...

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...

Coactivators

Studies in the NR field have identified families of proteins known as coactivators and corepres-sors, which modulate the function of transcription factors.79,80 Coactivators act by binding to the receptor in a ligand-dependent fashion and enhance ligand-dependent gene transcription. Overexpression of these coactivators can enhance the transcription of androgen-responsive genes in vitro. Conversely, downregulation of the corepressors is postulated to achieve the same effect. Many NR coactivators...

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...

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....

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...

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...

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...

Estrogen Progesterone and Androgen Receptors

The steroid and corticosteroid hormone receptors are responsible for controlling a number of reproductive and homeostatic systems, respectively. The sex steroid receptors ER, PR, and AR direct transcription of genes involved in sexual development, differentiation, and specification (Tables 3.4, 3.5). As a result of their growth-promoting activities in these processes, these receptors are pharmacologically targeted in a number of neoplastic reproductive tissues. Receptors ERa and ERjS are...

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,...

Familial Clustering Of Hormoneresponsive Cancers

Our primary topic of discussion is the role of inherited variation in gene sequence and its impact on cancer risk in the general population. We begin by examining the evidence that genetics (inherited variation in genome sequence) actually plays a role in the risk of cancer. The strongest data involve familial aggregation, showing that rates of disease are higher in the families of cancer patients than in the population at large. Of course, families are characterized by shared environment as...

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...

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...