CHT use has been demonstrated to confer an increased risk of breast cancer. Genetic variation in hormonal pathways may modify the effect of CHT on breast cancer risk. Using 1237 cases and 1015 controls from two population-based case-control studies of breast cancer, we investigated the effect of genetic variation in 7 genes within the progesterone pathway using a tagSNP and functional SNP approach and 5 genes within the catechol estrogen pathway. Within single gene analyses we observed breast cancer risk to be modestly associated with one SNPs in each GSTP1 (rs1695: OR = 1.4 [95% CI: 1.02-1.9] for carriers of A allele); CYP1B1 (rs1056827: OR = 1.7]95% CI:1.2-2.5] for T homozygotes); SRD5A1 (rs248793: OR=1.2 [95% CI: 1.02-1.5] for G homozygotes) and PGR (rs492457: OR=1.5 [95% CI: 1.01-2.1] for carriers of the A allele). We found that the breast cancer risk associated with SNPs was particularly strong in long-term CHT users. In a multi-gene model including two genes with single gene effects within the estrogen pathway (CYP1B1*2 and GSTP1), breast cancer risk was 1.6 (95% CI: 1.03-2.4) times higher for carriers of 1 high risk genotype and 2.8 (95% CI: 1.5-5.3) times higher for women with 2 high risk genotypes compared to women with 0 high risk genotypes. The impact of high risk genotypes was stronger in long-term CHT users, particularly in long-term, current CHT users (OR=5.6 [95% CI: 1-5-20.6]). These results suggest that breast cancer risk among CHT users is modified by variation in genes within hormonal pathways.

ABSTRACTConsiderable evidence has accrued from in vitro, clinical, and epidemiologic studies indicating that cumulative lifetime exposure to elevated levels of circulating ovarian hormones, including estrogens and progesterone, is a significant contributing factor in breast carcinogenesis. Pregnancy represents a crucial time period that substantially impacts a woman's lifetime risk of breast cancer, with younger age at first pregnancy and multiparity conferring a protective effect on long-term risk. The exact mechanisms by which pregnancy may reduce risk have been the focus of widespread research, with considerable emphasis on the contribution of hormonal influences. Particular maternal experiences or complications in pregnancy may be indicative of altered hormonal profiles. These pregnancy-related characteristics could potentially serve as proxies for distinct hormone exposures, and provide insight into the role that estrogens may have on breast cancer risk.^The goal of this doctoral dissertation project was to investigate and characterize the association between breast cancer risk and five pregnancy-related characteristics, including pregnancy-induced hypertension, preeclampsia or eclampsia/toxemia, gestational diabetes, pregnancy-associated weight gain, and pregnancy-related nausea and vomiting (NV). Given that these pregnancy-related characteristics are suspected to reflect distinct hormone profiles during and perhaps beyond pregnancy, including marked differences in estrogen exposures, we also examined genetic variation in key estrogen-metabolizing enzymes in relation to these characteristics to determine if genotype modified breast cancer risk. We evaluated a total of seven single-nucleotide polymorphisms in five genes coding for the following enzymes: cytochrome P450s CYP17, CYP1A1, and CYP1B1; catechol-O-methyltransferase; and glutathione-S-transferase P1.^Overall, a total of 2,918 women with at least one reported pregnancy were included in these analyses (1,001 cases with primary, incident, histologically-confirmed breast cancer and 1,917 controls frequency matched by age and race). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models, adjusting for suspected confounders. Pregnancy-related nausea and vomiting during any pregnancy was associated with a statistically significant reduction in breast cancer risk in premenopausal (OR 0.61; 95% CI 0.42-0.90) and postmenopausal (OR 0.73; 95% CI 0.58-0.92) women. Significant and consistent inverse associations were observed with greater percentage of pregnancies in which nausea and vomiting occurred, increased NV severity, and NV lasting longer into pregnancy. These associations did not differ by estrogen receptor (ER), combined ER and progesterone receptor (ER/PR), or human epidermal growth factor receptor 2 (HER2) expression status.^No significant associations with breast cancer risk were found for any of the other pregnancy-related characteristics. Carriers of the rare allele for the functional CYP1B1 rs1056836 SNP, a genotype which codes for enhanced enzyme activity, exhibited marginally positive associations with the likelihood of NV experience during pregnancy compared to common homozygous genotypes (OR1.22, 95% CI: 0.98-1.52 for the GG/GC compared to CC genotype). Significant multiplicative interactions between pregnancy-associated NV and this genotype in relation to breast cancer risk were found in both premenopausal and postmenopausal populations.^While null or slightly elevated risks were observed with NV among women with the common homozygous CC genotype, statistically significant reductions in breast cancer risk were observed for those with genotypes containing the rare G allele (OR 0.54, 95% CI: 0.32-0.91 [p for interaction = 0.036] in premenopausal women and OR 0.57, 95% CI: 0.41-0.78 [p for interaction = 0.011] in postmenopausal women). The findings presented herein suggest that nausea and vomiting during pregnancy may be associated with a reduction in breast cancer risk. Although there is no evidence of independent associations between estrogen-metabolizing enzyme genotypes and breast cancer risk, there may be associations between CYP1B1 polymorphisms and NV. Effect modification by CYP1B1 rs1056836 genotype on the association between NV and breast cancer risk provides evidence of a possible mechanistic role for estrogen or its metabolites.

Focuses on the challenges of determining the mechanistic basis for the role of hormones in the etiology of postmenopausal breast cancer. This book intends to bring attention to the advancements and challenges facing effective prevention and treatment of this disease.

This volume provides a comprehensive review of established and novel biomarkers across the continuum of breast cancer. The volume covers topics related to breast cancer risk and prevention, prediction of response to today’s standard therapies, and markers capable of influencing treatment decisions in the near future. Chapter authors combine their wide-ranging expertise to review the current status of the biomarker and to offer their individual perspectives on how biomarkers may be used in future treatments and research. Breast cancer continues to be the most common malignancy diagnosed in women in the Western world. While there are multiple treatment approaches for breast cancer, today more than ever we recognize that each tumor is unique. The challenge ahead is to consider how to best use validated and novel biomarkers to select the most appropriate treatment(s) for individual patients.

The Roundtable on Environmental Health Sciences, Research, and Medicine wanted to address the link between environmental factors and the development of cancer in light of recent advances in genomics. They asked what research tools are needed, how new scientific information can be applied in a timely manner to reduce the burden of cancer, and how this can be flexible enough to treat the individual.

OBJECTIVE: To evaluate and update the prior review evaluating the risk of breast cancer and breast cancer (BCA) death associated with the use of postmenopausal hormone replacement therapy (HRT) by reviewing the medical literature which has been published since the last US Preventive Services Task Force update. DATA SOURCE: All English language studies identified in the Medline database from 1992-2000 and all previously published meta-analyses. In addition, reference lists of key articles, letters, and editorials were reviewed for all related studies, including those pre-dating the database search. STUDY SELECTION: All studies that evaluated breast cancer incidence or mortality as a primary or secondary outcome in association with hormone replacement therapy published between 1992-2000. Studies evaluating the effect of hormone replacement therapy on breast density were also reviewed. DATA EXTRACTION: The following studies met inclusion criteria: 8 meta-analyses from the years 1988-1997, 1 nested case-control study, 14 case-control studies, and 15 cohort studies all evaluating breast cancer incidence, mortality, or both. Of the 15 cohort studies, 10 represented unique cohorts and of the 14 case control studies, 2 involved updates of the same case set. Data from each study were abstracted to prepared forms. When more than one study from the same population was reported, data from the most recent publication were reviewed. If data from the same population were analyzed by cohort and by case-control analysis, both results were reported if they evaluated different outcomes. In addition, several studies evaluating breast density and HRT were reviewed, and the best studies summarized. DATA SYNTHESIS: For ever or short-term use of estrogen, 7 of the 8 meta-analyses, 8 of the 11 case-control studies, and 6 of the 7 cohort studies evaluating incidence showed no increase in breast cancer with hormone replacement therapy. Of the original studies reviewed evaluating incidence, 12 of 19 showed no increased risk of breast cancer with long duration ERT or HRT use. However, 5 of the meta-analyses showed increased risk with duration over 5 years and 2 important cohort studies showed increased risk with longer duration use. Eleven original studies evaluated combined estrogen and progestin, and one showed increased risk of BCA with short-term use; 3 of the 5 evaluating duration with combined therapy showed increased risk that was statistically significant. Current use of ERT was associated with significantly increased risk of breast cancer in two of the best cohort studies; use of combined therapy was associated with increased risk in 3 studies. Six recent cohort studies (1992-2000) evaluated breast cancer mortality in association with hormone use: 1 showed increased risk of death, 4 showed decreased risk of death, and one showed no association. Several recent studies show that post-menopausal estrogen therapy is associated with increased breast density by mammography and that adding progesterone to estrogen results in even greater increases in breast density. Finally, there is evidence suggesting an important interaction between HRT and alcohol use and HRT and lower body weight. CONCLUSIONS: The association of short-term hormone replacement therapy with the development of breast cancer is uncertain based on multiple studies with inconsistent findings. Among studies indicating increased risk, the risk is largely confined to current and long-term use (>5-10 years), and the risk is relatively small (RR 1.2-1.5). Reduced mortality is a fairly consistent finding among the studies evaluating breast cancer mortality and HRT use. The addition of progesterone to estrogen and current, as well as long-term, use may be associated with breast cancer risk above that of estrogen itself. Although the biological plausibility of an association between postmenopausal hormone use and breast cancer is high, the studies showing risk or benefit from the use of post-menopausal hormones are limited by the observational nature of the epidemiologic data existing to date. Data from randomized controlled trials are needed to validly evaluate the relationship.

The Women's Health Initiative (WHI) clinical trial was the first randomised, double blind, placebo-controlled disease prevention trial to demonstrate epidemiological evidence of a casual link between the use of combined hormone replacement therapy (cHRT) comprising conjugated equine estrogens (CEE) and the synthetic progestin medroxyprogesterone acetate (MPA) and increased breast cancer risk in post-menopausal women. Since the first WHI report in 2002, other observational studies have demonstrated that it is the addition of the synthetic progestin in the cHRT that is associated with an increase in breast cancer risk. The focus of this thesis was to investigate the following hypothesis formulated in the Dame Roma Mitchell Cancer Research Laboratory, which proposed that MPA possesses antagonistic actions on androgen receptor (AR)-signalling and thereby can disrupt the protective effect of androgens in the breast, thus leading to an increased risk of breast cancer. Androgens have been associated with a growth restrictive role in breast tissue in both humans and animals and are now emerging as key hormonal pathways involved in the pathogenesis of breast cancer. The objectives of this thesis were firstly to determine the relationship between the use of cHRT containing MPA and breast cancer incidence in Australian women, and secondly to perform biological studies to investigate the effect of AR-action in breast epithelial cells. Initial findings described in this thesis led to the identification of a positive association between the use of cHRT preparations containing MPA and breast cancer incidence in Australian women. Subsequent biological based studies were undertaken with non-malignant breast tissues samples from pre- and post- menopausal women in an ex vivo breast explant tissue culture experimental model and the oestrogen receptor (ER), progesterone receptor (PR) and AR positive ZR-75-1 breast cancer cell line to investigate the actions of MPA on AR-signalling and cancer-related intracellular signalling pathways. Collectively these studies demonstrated that the actions of MPA can impede the anti-proliferative actions of DHT in both human postmenopausal non-malignant and malignant breast epithelial cells via AR-mediated actions. Furthermore, the combined actions of DHT and MPA were also shown to de-regulate cancer-related intracellular pathways compared to individual hormone treatments. The findings described in this thesis provide novel results indicating that MPA may promote the development of breast cancer in post-menopausal women taking cHRT via AR-mediated actions and that use of this form of hormone therapy remains a major public health concern.

In this systematic evidence review, we evaluate data on the relationship between the use of postmenopausal hormone replacement therapy (HRT) and the risk of breast cancer (BCA). The context of this review is in the overall evaluation of postmenopausal hormone replacement therapy as chemoprophylaxis for chronic conditions. The results from this report will be used as part of an overall report on the risks and benefits of hormone replacement therapy for postmenopausal women. Hormone replacement therapy is used in the United States and worldwide to treat symptoms of menopause and to prevent chronic conditions such as osteoporosis. It is one of the most commonly prescribed drugs in the U.S.; a recent survey in the U.S. of postmenopausal women ages 50 to 75 showed that nearly 38% of women were currently using estrogen or hormone replacement therapy (58.7% of those with prior hysterectomy and 19.6% without hysterectomy). A major and as yet unanswered clinical question is whether hormone replacement therapy increases a woman's risk of breast cancer. This issue is a critical one because the use of HRT is prevalent and because breast cancer is a relatively common disease, so that even a small increase in breast cancer in association with hormone use could significantly influence public health. The importance of endogenous estrogen in the development of breast cancer has been evaluated and confirmed in multiple studies of differing methodologies. Studies in animals have shown that breast cancer can be induced by the administration of estrogen. Among humans, some studies have shown that women with increased levels of circulating estrogen are at higher risk for the subsequent development of breast cancer. Other studies have had conflicting findings, and some have shown this relationship in postmenopausal women only. Reproductive events are important risk factors for breast cancer. Those shown to increase risk include early menarche and late menopause, both of which prolong exposure to higher levels of estrogen as well as other reproductive hormones. Other reproductive experiences, such as late age at first pregnancy and nulliparity, increase breast cancer risk. Oopherectomy among premenopausal women is protective against breast cancer, possibly because of reduced exposure to estrogen. Other risk factors also suggest an important role for estrogen in BCA development. In postmenopausal women, obesity, which correlates with increased estrogen levels, is also associated with an increased risk of BCA. Recent studies have also shown that increased bone density, possibly a reflection of lifetime estrogen exposure, is associated with increased rates of breast cancer. Finally, age-adjusted rates of increase in breast cancer incidence slow at menopause when estrogen levels fall. There are several critical key questions to consider when evaluating the research describing the role of exogenous estrogen or estrogen/progesterone in breast cancer development and prognosis. First, is either estrogen alone or estrogen with progesterone associated with a change in breast cancer mortality? Second, does short-term estrogen use increase the risk of breast cancer? The third question, which is most relevant to the use of estrogen to prevent chronic conditions, is whether long-term estrogen increases breast cancer risk. The fourth question, which reflects the current standard of practice, is whether the combination of estrogen and progesterone, either short-term or long-term, increases the risk of breast cancer. Fifth, is current use of estrogen or hormone replacement therapy associated with increased risk of breast cancer? Sixth, are there subpopulations of women who might be at increased risk of breast cancer when using HRT? Finally, because increased breast mammographic density is independently associated with an increase in breast cancer risk, as well as with decreased accuracy of mammography, does estrogen or estrogen/progestins change breast density?