New Opportunities for PCA Prevention

The convergence of PCA epidemiology, indicating a possible role for prostate inflammation, and a significant role for the diet, in PCA development, with molecular pathology, revealing that neoplastic prostate cells may have acquired an increased vulnerability to carcinogen damage, provides an opportunity for the discovery and development of rational new approaches to PCA prevention. Possible strategies include reduced exposure to genome damaging oxidants and other carcinogens, and intake of...

EGCG Modulation of Food Intake and Endocrine Systems

The mechanism by which EGCG suppresses prostate tumor growth may be very complex. Many in-vitro effects of EGCG, including inhibition of cancer cell mobility, inhibition of key enzymes and protein factors, induction of apoptosis, and inhibition of angiogenesis, have been shown (1). It is very difficult to assess whether these in-vitro observations are related to in-vivo effects because EGCG and other catechins can interact non-specifically with enzymes or other macromolecules as well as...

Results and Discussion

To specifically silence the FAS gene, LNCaP cells were transfected with FAS siRNA as previously described (27). As a control for specificity ofRNAi, LNCaP cells were transfected with siRNA-targeting luciferase, which is not expressed by LNCaP cells. Western blot analysis demonstrated that expression of FAS was severely decreased in LNCaP cells transfected with FAS siRNA compared to control cells transfected with luciferase siRNA (Figure 2). Figure 2. Effects of FAS RNAi on FAS expression. LNCaP...

Henri Rochefort Majida Esslimani Sahla and Dany Chalbos Introduction

The assumed role of progesterone and progestins on mammary glands and human breast carcinogenesis has varied between laboratories and countries and is still controversial. Progestins inhibit estrogen (E) action in cell lines and provide protection against the mitogenic effect of Es in endometrium, which is why they are required to overcome the mitogenic activity of E in hormone replacement therapy (HRT) of non-hysterectomised postmenopausal women. The effect of progestins on mammary...

Summary

Docking or adapter proteins link signals emanating from receptors to other downstream intracellular molecules and amplify the initial signal. Therefore, the activation of a docking protein can indicate the prior activation of a receptor, such as a receptor tyrosine kinase (RTK). The Gab-1 (for Grb-2-associated binder-1) docking protein is a substrate for many different RTKs. As part of our effort to define the signaling pathways stimulated by 17 (3-estradiol (E2) and progesterone (P) in the...

William R Miller Introduction

There is compelling evidence that estrogens (Es) both increase risk of developing breast cancer (BC) and maintain the growth and progression of established tumors (1). Recently, drugs have been developed which specifically and potently block E biosynthesis (aromatase inhibitors). These agents now occupy a central role in the treatment of postmenopausal patients with BC, and are being considered as preventative agents in women at high risk ofthe disease. The success ofthese drugs is founded on...

Aromatase Inhibitors and Treatment of Breast Cancer

Neoadjuvant protocols in which therapy is given with the primary cancer remaining within the breast allow tumor responses to be assessed in individual patients by monitoring changes in tumor volume during treatment. Impressive anti-tumor effects have been observed in selected groups of patients with estrogen receptor (ER)-a rich cancers. (19, 35) (Table 2). Marked reduction in tumor size provides clinical benefits, and many patients who initially required mastectomy or were inoperable can be...

Major Risk Factors

PCA is probably the leastunderstood epidemiologically of all major cancers. In fact there are still only three fully established risk factors 1) Age. PCA is the most age-related of all epithelial cancers. Historically, it has been extremely rare prior to age 40 (more cases are now being diagnosed with the introduction of prostate specific antigen (PSA) screening to detect pre-clinical disease), but thereafter the increase in incidence with age is greater than for any other cancer (incidence...

Materials and Methods

Reverse Transcription Polymerase Chain Reaction (RT-PCR). An autocrine paracrine role for CCK in GH3 rat pituitary tumor cells has been reported via the CCK-B receptor subtype. To examine the suggested presence of the CCK-B and the possible involvement of the CCK-A receptor subtypes on human pituitary adenomas, total RNA was extracted from 30 human functionless pituitary tumours (specimens originated from Queen Elizabeth Medical Centre, University of Birmingham, UK), reverse transcribed into...

The Role of Progesterone in the Etiology of Breast Cancer

While E's role in the etiology of BC has been extensively studied, and E has been shown to play multiple roles in BC pathways, less is known about the relationship between P and BC etiology. Initially, P was thought to protect the breast from cancer based on its anti-proliferative effects on the endometrium. However, several recent studies suggest that P is involved in multiple pathways associated with BC. In 1994, Shi, et al. (39) summarized evidence documenting the role of P in the initiation...

Results

P300 and PCA. p300 has been shown to interact with the AR during its ligand-dependent activation in PCA cells (11). The same study shows that a point mutation in the acetylation site ofthe AR abrogated the A-dependent transactivation of the receptor. However, p300 role in A-independent transactivation of the AR remains to be elucidated. One growth factor involved in PCA progression is, as be mentioned above, IL-6. This cytokine has been found to transactivate AR in the presence and absence of...

Introduction

Estrogens influence growth, differentiation, and the function ofmany target tissues in female and male reproductive organs. Their best-described mechanism ofaction is through ER-mediated gene transcription. This ligand-activated transcription factor is known to exist in two forms, a and P, and multiple splice variants of both are present in a variety of tissues (1-3). The presence of these ERs and their isoforms adds a high degree of complexity to their action, which may be cell tissue...

Differences Between SERMs and Aromatase Inhibitors

SERMs and aromatase inhibitors are often thought of as being equivalent however differences in mechanism of action may lead to variations in biological and clinical effects. For example, aromatase inhibitors reduce endogenously synthesized Es in contrast, SERMs generally do not inhibit synthesis, and E levels remained unaltered (60), or, in the case of pre-menopausal women, may increase (61, 62). This difference may be important because metabolites ofnatural Es can have influences independent...

Hormonal Prevention of Breast Cancer Mimicking the Protective Effect of Pregnancy

Hormonal prevention strategies have used exogenous hormonal treatment to mimic the protective effect of pregnancy against BC. Huggins, et al. (29) reported that high levels of E2 and P given for 30 days beginning 15 days after DMBA administration inhibited MC in SD rats. They proposed that treatment with high levels of these hormones destroyed the potential cancer cells. Grubbs, et al. (30, 31) and McCormick and Moon (32) demonstrated that treatment of SD rats with high levels of and P, or...

Development of Short Term Hormone Treatments for Prevention of MNUinduced Mammary Carcinogenesis in Rats

The Protective Effect of Parity can be Mimicked by Short-term Treatment with E2 or E2 + P. Pregnant rats are exposed to very high circulatory levels of E2 and P that induce lobulo-alveolar differentiation in the mammary gland. To mimic this protective effect of pregnancy, we treated 7-week-old virgin rats with MNU followed by treatment with or perphenazine (PPZ, dopamine receptor inhibitor) for 3 weeks beginning at 9 weeks of age (10). Both of these treatments caused late pregnancy-like lobule...

Aromatase Transgenic Mice are Susceptible to Carcinogens

To test the hypothesis that tissue E-induced preneoplastic changes induced may be susceptible to carcinogens like DMBA, and that exposure to these carcinogens may result in acceleration and or increase in the incidence of BC (21). Exposure to a single sub-threshold concentrations of DMBA (0.5 (ig mouse) resulted in development of MG tumors in 25-1 of the transgenic animals and non in wild type mice. All the DMBA-exposed transgenic females had microscopic evidence of tumor formation neoplastic...

Causative Factors for Refractoriness of Parous Rats to Mammary Carcinogenesis

Parous Rats Treated with MNU Have a High Incidence of Latent Mammary Cancers. In collaboration with Dr. Airo Tsubura, the role ofparity before and after MNU treatment was studied (24). Pregnancy and lactation before (22 ) or after (25 ) MNU treatment reduced the incidence of frank MCs compared to age- matched nulliparous females (72 ) and (94 ), respectively. At termination, rats that underwent pregnancy prior to MNU (67 ) or after MNU (50 ) both had high incidences of microscopic latent...

Hyperplastic and Premalignant Lesions Precursors and Markers of Increased Risk of Breast Cancer

The various identified breast lesions of interest are listed in Table 1 and 2 along with their major known associations. The precise separation of these lesions in practical histopathology has evolved over time, and as a practical matter in clinical medicine, there remain some differences in application in the clinical arena. Basically, most ofthe studies presented in this review have been accepted by major pathology associations in North America and Britain. The ductal carcinomas in-situ...

Atypical Adenomatous Hyperplasia AAH or Adenosis

The data that exist on the prevalence of atypical adenomatous hyperplasia (AAH) also known as adenosis (53,54) is controversial. The vast majority ofadenosis foci are found in the TZ. They are usually associated with benign prostatic hyperplasia (BPH) nodules and may share some morphologic features with well-differentiated carcinoma (55). The prevalence of AAH in the literature is highly variable (from 1.6 to 19.6 ) (56). A study of a series of needle biopsy specimens reported a lower...

References

Sakr WA, Grignon DJ, Crissman JD, et al (1994) High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of20-69 an autopsy study of249 cases. In Vivo 8 439-443. 2. Hsing AW, Deng J, Sesterhenn IA, et al (2000) Body size and prostate cancer a population-based case-control study in China. Cancer Epidemiol Biomarkers Prev 9 1335-1341. 3. Gann PH, Ma J, Giovannucci E, et al (1999) Lower prostate cancer risk in men with elevated plasma lycopene levels...

The Androgen Receptor Gene

The AR is a member ofthe superfamily of steroid receptors and like most receptors in this family has a DNA binding domain, a hormone binding domain and a transcription modulatory domain which for the AR is completely encoded by the large exon 1 of the AR gene (15). The AR gene maps to the long arm of the X chromosome (15). Within exon 1 are two highly polymorphic tri-nucleotide repeats a (CAG)n and a (GGC)n . We became interested initially in the CAG repeat with the recognition that an...

Estrogen and its Receptors

Estrogens and estrogen receptor (ER) have been implicated in the pathogenesis and progression of ovarian cancer based on epidemiological and experimental observations (41-43). Even though estrogens plus progestins taken as an oral contraceptive during the premenopausal period in women are protective, when used in postmenopausal years as hormone replacement therapy, estrogens may increase the risk of ovarian cancer (7). Although no difference in risk was observed in women who had used estrogens...

Parous Phenotypes

International studies by MacMahon, et al. (12,13) suggested that women undergoing a full-term pregnancy before the age of 18, with or without lactation, have about one-third the risk for developing BC compared to women undergoing a first pregnancy after the age of 35. Recently, meta-analysis of BC risk reduction related to breast feeding has been performed based on data from 47 epidemiological studies from 30 countries (3). Their analysis shows that breast-feeding is associated with a...

Aromatase Overexpression Results in Gynecomastia and Leydig Tumors in Male Transgenic Mice

Overexpression of ARO in male transgenic mice results in increased MG epithelial growth as early as 3 mo of age with well-organized ductal structures and lobulo-alveolar growth. We did not observe further progression of hyperplastic and dysplastic changes in the ARO transgenic mice with age (31). In addition, our data demonstrated that the Overexpression of ARO plays a significant role in the formation of Leydig cell tumors, and that these cells are targets for estrogenic action and are...

Centrosome Amplification in Cancer

Recent studies implicate centrosome abnormalities in the pathogenesis of cancer (4, 10-14). The term centrosome amplification refers to centrosomes that appear larger than normal, centrosomes that contain more than four centrioles, and or when more than two centrosomes are present within a cell. In addition to these structural abnormalities, amplified centrosomes also show protein hyperphosphorylation and altered functional properties such as an increased microtubule nucleating capacity (4, 8,...

Mechanisms of Cyclin E Deregulation in Cancer

The first report of cyclin E gene amplification as tumor-linked mechanism for elevation of cyclin E expression was based on a breast cancer (BC) derived cell line (15). Subsequently cyclin E gene amplification has been reported at varying frequencies in a variety of different tumor types, particularly gastrointestinal and ovarian cancer (16-18). In BC, however, cyclin E gene amplification is rare (16). We therefore sought to determine if deregulation of cyclin E could be mediated by defects in...

The Promotional Environment for Mammary Carcinogenesis is Decreased in the Parous Rats Compared to that of Nulliparous

The tumorigenicity of MNU-treated MEC transplanted to virgin or parous Lewis rats was tested (41). The objective ofthese studies was to determine whether the systemic environment in the parous rat is supportive of tumorigenesis. Young nulliparous Lewis rats (50-60 days of age) were treated with MNU. One month after treatment, the treated mammary glands were removed and enzymatically dissociated. The purified epithelial cells were transplanted per site) to the...

Concluding Remarks

Our studies revealed that our current understanding of PCA progression is very inadequate, especially for designing clinical treatment of PCA after the initial hormonal therapy has failed and A-independent tumors reappeared. The four stages we have identified take a long period of time, over years, for progression, which resembles the PCA patient situation. Based on our findings, at the initial stage after recurrence of A-independent tumors (R1-form), As at physiological concentration can...

ProgesteronePR Signaling in Mammary Carcinogenesis

Most of the classical studies on the developmental biology of the normal mammary gland and mammary oncogenesis have been done in rodents. Conclusions derived from these studies have been found to be applicable to the human condition (19). Furthermore, the pattern of PR localization in normal mouse mammary glands is similar to that reported previously for human breast, i.e., (a) PR expression in the epithelial cells is heterogeneous, and (b) the connective tissue surrounding these epithelial...

What is the Significance of FAS Overexpression in Cancer Cells

Is FAS over-expression a marker only associated with aggressive solid tumours or is it actively engaged in mammary carcinogenesis FAS activity and endogenous fatty acid synthesis are required for normal embryonic development since FAS gene knock-out is lethal in mice (43). In normal adult cells, except in lactating mammary glands (30), FAS activity is low since fatty acids are mostly provided by food and imported from local vascularization (47). The use of our specific FAS antibodies on...

Detection of Id1 Overexpression in PCA in the Rat Model

Using this model, we studied the gene expression profile during prostate carcinogenesis using a cDNA array method. The results were confirmed by RT-PCR, western blotting, and immunohistochemical (IHC) analyses. Seventeen genes were differentially expressed, and three of them with the highest level of overexpression were selected for further analysis. They included Testosterone-repressed prostatic message-2 (TRPM-2), matrix metalloproteinase-7, (MMP-7), and inhibitor ofdifferentiation or DNA...

Role of Estrogens in the Development of Breast Cancer

The mechanism by which Es increase risk of overt BC is still the subject of debate (Figure 4). Es can stimulate the proliferation of breast epithelial cells, leading to genetic mistakes and a transformed cellular phenotype (72). Additionally, Es can accelerate the growth of occult cancers resulting in increased incidence of overt disease (73). These promotional properties of Es appear to be largely mediated through ER signaling system. Consequently, both SERMs and aromatase inhibitors should...

Estrogens Aromatase and Risk of Breast Cancer

Many of the etiological factors associated with BC have a hormonal component (1). Additionally, high BC risk has been related to increased E exposure from either endogenous (41-46) or exogenous sources (47, 48). Polymorphisms in the aromatase gene in women at high BC risk (49,50), and enhanced aromatase activity in the breasts of women with BC (51, 52) have been reported. Conversely, E deprivation may protect against the disease (53,54). For example, ovarian ablation before the age of 35 years...

Aromatase Inhibitors and Prevention of Breast Cancer

The above rationale and positive results with SERMs underpin the case for trials of aromatase inhibitors in the preventative setting. However, the potent endocrine effects ofthird generation inhibitors make long-term monitoring of bone and lipid profiles mandatory. Ongoing adjuvant trials with aromatase inhibitors provide information on the incidence ofnew contralateral BCs and side-effect profiles. The large ATAC trial shows a significant reduction in contralateral cancer in the aromatase...

Mutations of the Androgen Receptor in PCA

In contrast to AR mutations detected in patients with androgen insensitivity syndromes, several structural changes of the AR in PCA lead to gain of function. This was first observed in LNCaP cells, whose mutant AR is efficiently activated by adrenal androgens, anti-androgens, and estrogenic or progestagenic steroids (17). In LNCaP cells, threonine at position 877 is mutated to alanine. The mutation changes the stereochemistry of the binding pocket of the AR. The first two mutations discovered...

Use of Human Breast Cancer Cell Lines to Detect Specific Receptor Induced Proteins

Before the development of DNA micro-array and SAGE approaches, the use of labelling of proteins synthesized in cell culture, before and after hormone stimulation, allowed us detection of several steroid hormone specific induced proteins, as defined by their molecular weight in SDS-PAGE, which could then be identified and studied in tumour samples to specify their significance in human carcinogenesis (16). Regarding progestins, using dose response curves and anti-hormones, we could not...

Christopher I Li Introduction

Sex hormones have been implicated in the etiology ofbreast cancer (BC) since the eighteenth century, when Ramazzini, an Italian physician, observed that nuns were more likely to develop BC than other women. Since that time, observational studies have documented that exposures with a hormonal component, including reproductive factors, use of exogenous hormones, and anthropometric characteristics, are among the most important and consistent BC risk factors. Thus, a further understanding of the...

The Mechanism of FAS Regulation by Progestin

The mechanism of FAS regulation by progestins was found to be direct, since it was not inhibited by cycloheximide, and rapid, with an increase oftranscription within 20 min. It is also post-transcriptional since progestins increased FAS mRNA stability (29,31). FAS was not induced by Es or glucocorticoids and different types ofprogestins used in HRT, including the pure progestin R5020 and MPA, were similarly active in the induction of FAS (18 and unpublished experiments). Progesterone however,...

Jeffrey L Salisbury Introduction

Aneuploidy and chromosomal instability (CIN) are defining features of most aggressive breast cancers (BC). One consequence of CIN is a constantly changing genetic makeup of cancer cells - this in turn is a major driving force behind cancer cell heterogeneity, tumor progression, and acquisition of resistance to chemotherapeutics. How CIN arises in cancer and the mechanisms underlying this process have become a topical focus of cancer research. Yet it was nearly a century ago that Theodor Boveri...

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...

EGCG Suppression of Prostate and Breast Tumors

Green tea consumption has been linked to lower incidence of some cancers in humans and animals. Epidemiological studies, however, have not provided consistent evidence about the anti-tumorigenic effect of green tea in humans. 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...

Establishment of Models for Studying Prostate Cancer Cell Progression

Because PCA is initially dependent on As for its growth, hormonal therapy (A deprivation), pioneered by Charles Huggins 60 years ago (20) using castration or more recently anti-androgens, has been a standard PCA therapy. Although over 70 of patients may benefit from this therapy, PCA recurs in most of these patients in one to three years as tumors that do not need A for growth (A-independent). For lack of effective therapy, patients die from this A-independent PCA. We believe that a better...

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...

The Molecular Pathogenesis of Human Prostate Cancer

DeMarzo, Theodore L. DeWeese, and William B. Isaacs 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,...

Antonio Llombartbosch

Director, Departamento de Patologia Facultad de Medicina y Odontologia Universidad de Valencia Valencia, Spain eBook ISBN 0-387-23761-5 Print ISBN 0-387-23783-6 2005 Springer Science + Business Media, Inc. Print 2005 Springer Science + Business Media, Inc. Boston No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Springer's...

Material and Methods

Mutation analysis was performed by denaturating gradient gel electrophoresis and PCR described by Guldberg, et al. (17). Plasmids and Mutagenesis. Human wt PTEN DNA, kindly provided by Dr. Steck (University of Texas, Houston), was subcloned into the pxmyc vector according to Lukas, et al. (18). PTENpxmyc mutagenesis was performed as previously described (19). Cell Culture and Transfection. The human androgen insensitive prostate cancer cell lines DU-145 and PC-3 were...

Acknowledgement

These studies were supported by NIH Grant CA 66541. References 1. Bresciani F (1968) Topography of DNA synthesis in the mammary gland of the C3H mouse and its control by ovarian hormones an autoradiographic study. Cell Tissue Kinetics 1 51. 2. Ferguson DJ, Anderson TJ (1981) Morphological evaluation of cell turnover in relation to the menstrual cycle in the resting human breast. Br J Cancer 44 177-181. 3. Going JJ, Anderson TJ, Battersby S, et al (1988) Proliferative and secretory activity in...

Deregulation of the Centrosome Cycle in Cancer

G1 S and G2 M checkpoints enforce the orderly completion of cell cycle events, and when triggered, they inhibit the formation and or activation ofCdks and thereby induce cell cycle arrest (63,64). Cell cycle checkpoints operate through the action tumor suppressor proteins p53 and Rb, and their downstream activation target Cdk2. Interestingly both p53 and Cdk2 may also physically reside at the centrosome, albeit only transiently (65,66). The physical presence ofkey proteins involved in...

The Antiestrogenic Activity of Progestins Good or Bad Significance

It is clear that progesterone is a natural anti-E, thus partially explaining its protective effect in endometrium. We showed this anti-estrogenic activity on BC in vitro, since R5020, a pure progestin, inhibited the E-induced growth of MCF7 cells 8 . However, proposals concerning mechanism ofthis anti-estrogenic activity have varied with time Induction of 17P-OH-steroid dehydrogenase 9 , increase of inactive E-sulfates 20 , down regulation ofthe ER, and inhibition of transcription of...

CMyc Deregulation in Cancer

Myc Deregulation

C-Myc overexpression is associated with neoplasms of different tissues, including breast 11,12 , neuroblastoma 13 , cervical carcinoma 14 , malignant melanoma 15 , prostate cancer 16 , osteogenic sarcoma 17 , and lymphoid cancer 6, 18, 19 reviewed in 20 . Thus, Myc protein overexpression is an important player in cellular transformation 21-25 . Figure 1. c-Myc-dependent locus-specific and karyotypic instability in neoplasia. Figure 1. c-Myc-dependent locus-specific and karyotypic instability in...

Controversies and Discrepancies Concerning Progestin Action on Mammary Glands

Progestin Pathway

There is a relatively high consensus among laboratories on the mitogenic effect of Es on the mammary gland, and coherence between in-vitro studies on cell lines, and in-vivo epidemiological data, even though the detailed mechanism is not yet fully understood. By contrast, the effects of progestins after menopause, i.e., whether good or bad, have been extensively debated according to the laboratory and country involved. This is mostly due to the fact that different progestins are being used and...

Id1 Activity and MAPK Signaling Pathway

Mapk Egr Pathway

Earlier, we have shown that expression of Id-1 may be associated with advanced stages of PCA 17 . This implicates that Id-1 may function as an oncogene. Our earlier studies further suggest that one of the oncogenic functions of Id-1 may be through inactivation ofpl61NK4a, leading to the dysfunction ofpl61NK4a Rb tumor suppressor pathway 18 . Recently, Id-1 has been shown to facilitate human fibroblasts escaping senescence through the Ras-Raf-MEK signaling pathway 19 . In addition, one of the...

Chromosomal Instability A New Paradigm for Estrogeninduced Oncogenesis

Li, Jeffrey Salisbury, and Sara Antonia Li Introduction Human sporadic breast cancer BC comprises gt 90 of all BC cases whereas familial BC is less than 10 1 . Despite its likely multifactorial origin, there is now pervasive evidence from epidemiological and animal studies, developed over the past several decades, that the causation of human sporadic BC primarily involves female sex hormones, particularly estrogens Es 1-8 . This view is consistent with long standing epidemiological...

Hormones Centrosomes and Genomic Instability in Mammary Carcinogenesis

Breast Cancer Carcinogenesis

Stenoien, and Thea Goepfert Introduction The centrosome, a cytoplasmic organelle acquired at fertilization via paternal inheritance, plays a vital role in cell division and in the maintenance of cell polarity throughout development. The importance of the centrosome in achieving proper orientation and segregation of duplicated chromosomes and assuring stability of the eukaryotic genome is well established. The centrosome can be recognized in the cytoplasm of most...

Cell Molecular Biology Breast Cancer

Bi-directional Regulation of Human Progesterone Receptors and the Mitogen Activated Protein Kinase Pathway in Breast Cancer Cell Models Emily Faivre, Ming Qiu, and Carol A. 381 Abnormal Properties of Mutants in the Hinge Region of ErV Implications in Breast Cancer Carlos Mart nez-Campa, Pedro Zuazua, Juana Mar a Garc a-Pedrero, Pedro Casado, Pedro S nchez Lazo, and Sof a Ramos 391 The Effects of Eicosapentaenoic Acid Upon Proliferation and 17 -Dehydrogenase Activity in MCF-7 Breast Carcinoma...

Haojie Huang and Donald J Tindall Introduction

Surgical or pharmaceutical ablation of testicular androgens has been the most effective treatment of metastatic prostate cancer PCA since 1941 1 . Both normal and malignant epithelial cells ofthe prostate undergo programmed cell death apoptosis in the absence of androgens 2, 3 . However, a majority of PCA patients usually relapse with tumors becoming refractory to androgen ablation therapy, suggesting that relapsed cells are able to resist androgen withdrawal-induced cell death 4 ....

Comparisons of Parous and Hormone Protected Rats Similar or Different

Parous rats are susceptible to carcinogen-induced initiation and develop a high incidence of latent mammary cancers. However, these rats are protected from promotion and develop a very low incidence of overt mammary cancers. We determine whether the phenotypes of rats receiving protective hormone treatment mimic the protective effect of parous rats. That is, whether or not protective hormone treatments result in phenotypes susceptible to carcinogen-induced initiation, and develop latent mammary...

Characteristics of ILC Compared to IDC

Pathologic, Immunohistochemical and Genetic Characteristics. Classic ILC was first identified and distinguished from other types of BC by the pathologists Foote and Stewart in 1941. Based on their histopathologic descriptions, classic ILC is characterized by slender linear strands of cancer cells in single file, which are present diffusely throughout the tissue 4 . Lobular tumor cells are also typically small and uniform in size, and often have a signet-ring shape. Alternatively, IDC has a more...

HCDC4 Mutation Leads to Deregulation of Cyclin E Relative to the Cell Cycle

Analysis of cyclin E in the breast tumor-derived cell line found to be mutated for hCDC4 SUM149PT indicated that the protein was overexpressed relative to non-transformed human mammary epithelial cells and most other BC derived cell lines 13 . However, more interestingly, when the SUM149PT cell line was analyzed by immunofluorescence microscopy all cells in an asynchronous population were cyclin E-positive. This is in contrast to other tumor-derived cell lines and non-transformed cells where...

The History of cMyc

C-Myc is the cellular counterpart ofthe viral oncogene v-myc that was identified as the transforming factor in avian retroviruses, MH-2, MC29 2 , CMII and OK 10 3 . Subsequently, it was discovered that bursal B-cell lymphomas in retrovirus-infected fowl were caused by retroviral integrations in or near the c-myc proto-oncogene, which caused constitutive expression of c-myc. In some cases, these transcripts originated at the promoter in the long terminal repeat LTR of the retrovirus 4 . In other...

Participants

Marcelo Aldaz The University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA Lorenzo Alonso Hospital Universitario de M laga, Madrid, SPAIN Leoncio Arribas Alpuente Hospital Universitario de M laga, Madrid, SPAIN Bynthia Maria Anose Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA Manuel Valladares Ayerbes Medical Oncology, Pathology and Research Units, Medicine Department, Juan Canalejo University Hospital, La Coru a,...