Modify Breast Cancer Risk Research Articles

Abstract P6-09-08: Exposure to multiple sources of polycyclic aromatic hydrocarbon and breast cancer incidence

Abstract Background. Previous epidemiologic studies, including our own, have consistently linked long-term exposure to single-source polycyclic aromatic hydrocarbons (PAHs) to increased breast cancer incidence. It is unclear whether single sources, specific groups, or all PAH sources should be targeted for breast cancer risk reduction. This study considers the impact on breast cancer incidence from multiple PAH exposure sources in a single model, which better reflects exposure to these complex mixtures. Methods. In a population-based case-control study conducted on Long Island, New York (N=1,508 breast cancer cases/1,556 controls), a Bayesian hierarchical regression approach was used to estimate adjusted posterior means and credible intervals (CrI) for the adjusted odds ratios (ORs) for PAH exposure sources, considered singly and as groups: active smoking; residential environmental tobacco smoke (ETS); indoor and outdoor air pollution; and grilled/smoked meat intake. Results. Most women were exposed to PAHs from multiple sources. In a hierarchical model, breast cancer incidence was positively associated with ETS from a spouse (OR=1.20, 95%CrI=1.03, 1.42) and residential synthetic firelog burning (OR=1.30, 95%CrI=1.06, 1.60). Additionally, PAH exposure groups, including ingestion (OR=1.45, 95%CrI=1.16, 1.79), indoor stove/fireplace use (OR=1.30, 95%CrI=1.02, 1.62), and total indoor sources (active smoking, ETS from spouse, grilled/smoked meat intake, stove/fireplace use, OR=1.46, 95%CrI=1.03, 2.05), were associated with increased breast cancer incidence. Conclusions. Groups of PAH sources, especially those for ingestion and indoor sources, were associated with a 30-50% increase in breast cancer incidence. PAH exposure is ubiquitous and a potentially modifiable breast cancer risk factor. Citation Format: White AJ, Bradshaw PT, Herring AH, Teitelbaum SL, Beyea J, Stellman SD, Steck SE, Mordukhovich I, Eng SM, Engel LS, Conway K, Hatch M, Neugut AI, Santella RM, Gammon MD. Exposure to multiple sources of polycyclic aromatic hydrocarbon and breast cancer incidence. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-08.

Abstract P1-07-05: Weight change across the life-course and breast cancer risk among pre and postmenopausal women

Abstract Obesity is well established as a cause of postmenopausal breast cancer incidence and mortality. In contrast, adiposity in early life is inversely related to breast cancer incidence. To better integrate understanding of these relations, we assess adiposity in childhood, in late adolescence, and in adult years, as well as change in weight in relation to total invasive breast cancer and subtype defined by receptor status. The Nurses' Health Study cohort was established in 1976 when 121,701 female US registered nurses ages 30-55 responded to a mailed questionnaire about risk factors for breast cancer including reproductive factors, hormone use, anthropometric variables, benign breast disease (BBD), and family history of breast cancer. The risk factors have been updated by repeat questionnaires every 2 years. We followed a cohort of 77,232 women from 1980 to 2006 (1,408,188 person-years), with routinely updated risk factor information, documenting 4,254 incident cases of invasive breast cancer. ER and PR status were obtained from pathology reports and medical records. A total of 2,065 ER+/PR+ tumors, 604 ER-/PR- tumors, 520 ER+/PR- tumors were identified among women with complete information on breast cancer risk factors. Weight at age 18 was inversely related to incidence of pre and postmenopausal breast cancer. The relative risk (RR) per 50lb weight difference at age 18 was 0.80 (95% CI = 0.73, 0.88). However, the inverse association is completely explained by weight at age 10. Weight at age 10 was more strongly inversely related to ER-PR- breast cancer, RR per 50lb difference in weight at age 10 = 0.48; 95% CI 0.32 – 0.74. Weight gain from 10 to 18 was not related to risk. After controlling for weight at age 18, weight loss of 10lb or more was significantly related to lower risk of breast cancer (RR=0.80; 0.66, 0.95) overall. The association was stronger for premenopausal breast cancer (RR=0.51; 0.30, 0.88). Long-term weight change was positively related to total incident breast cancer risk and most clearly to postmenopausal cancer (RR per 50lb weight gain since age 18 =1.26; 1.19-1.34). Weight gain during premenopausal years (weight at menopause minus weight at age 18), and after menopause, were both directly related to increased risk. Weight gain of 30 or more pounds during premenopause increased risk of postmenopausal breast cancer compared to less than 10lb weight change (RR=1.25; 1.14-1.38) and weight gain of 30 or more pounds after menopause carried similar increase in relative risk (RR=1.24; 1.10-1.41). These results were unchanged after control for weight at age 10, and were stronger for ER+PR+ breast cancer. The associations for long-term weight gain and postmenopausal breast cancer are stronger for never vs. ever users of hormone therapy, but are significantly positively associated in both groups. In conclusion, adiposity in childhood has a protective lifelong relation to breast cancer risk most clearly seen for ER-PR- disease. There are deleterious effects of long-term weight gain both pre- and post-menopause. Weight loss in premenopausal years significantly reduces risk of breast cancer. Weight change can importantly modify breast cancer risk. Citation Format: Colditz G, Eliassen H, Toriola A, Hankinson S, Willett W, Rosner B. Weight change across the life-course and breast cancer risk among pre and postmenopausal women. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-05.

Exposure to multiple sources of polycyclic aromatic hydrocarbons and breast cancer incidence

BackgroundDespite studies having consistently linked exposure to single-source polycyclic aromatic hydrocarbons (PAHs) to breast cancer, it is unclear whether single sources or specific groups of PAH sources should be targeted for breast cancer risk reduction. ObjectivesThis study considers the impact on breast cancer incidence from multiple PAH exposure sources in a single model, which better reflects exposure to these complex mixtures. MethodsIn a population-based case-control study conducted on Long Island, New York (N=1508 breast cancer cases/1556 controls), a Bayesian hierarchical regression approach was used to estimate adjusted posterior means and credible intervals (CrI) for the adjusted odds ratios (ORs) for PAH exposure sources, considered singly and as groups: active smoking; residential environmental tobacco smoke (ETS); indoor and outdoor air pollution; and grilled/smoked meat intake. ResultsMost women were exposed to PAHs from multiple sources, and the most common included active/passive smoking and grilled/smoked food intake. In multiple-PAH source models, breast cancer incidence was associated with residential ETS from a spouse (OR=1.20, 95%CrI=1.03, 1.40) and synthetic firelog burning (OR=1.29, 95%CrI=1.06, 1.57); these estimates are similar, but slightly attenuated, to those from single-source models. Additionally when we considered PAH exposure groups, the most pronounced significant associations included total indoor sources (active smoking, ETS from spouse, grilled/smoked meat intake, stove/fireplace use, OR=1.45, 95%CrI=1.02, 2.04). ConclusionsGroups of PAH sources, particularly indoor sources, were associated with a 30–50% increase in breast cancer incidence. PAH exposure is ubiquitous and a potentially modifiable breast cancer risk factor.

Progestin and breast cancer risk: a systematic review.

This systematic review summarizes research on the use of progestin and breast cancer risk. Although mainly used for contraception, progestin can help treat menstrual disorders, and benign breast, uterine, and ovarian diseases. Breast cancer is the leading site of new, non-skin, cancers in females in the United States, and possible factors that may modulate breast cancer risk need to be identified. ProQuest (Ann Arbor, MI) and PubMed-Medline (US National Library of Medicine, Bethesda MD, USA) databases were used to search for epidemiologic studies from 2000 to 2015 that examined the association between progestin and breast cancer. Search terms included epidemiologic studies + progesterone or progestin or progestogen or contraceptive or contraceptive agents + breast cancer or breast neoplasms. A total of six studies were included in the review. Five of the six studies reported no association between progestin-only formulations (including norethindrone oral contraceptives, depot medroxyprogesterone acetate, injectable, levonorgestrel system users, implantable and intrauterine devices) and breast cancer risk. Duration of use was examined in a few studies with heterogeneous results. Unlike studies of other oral contraceptives, studies indicate that progestin-only formulations do not increase the risk of breast cancer, although the literature is hampered by small sample sizes. Future research is needed to corroborate these findings, as further understanding of synthetic progesterone may initiate new prescription practices or guidelines for women's health.

Personalizing Aspirin Use for Targeted Breast Cancer Chemoprevention in Postmenopausal Women

ObjectiveTo evaluate the association of aspirin and other nonsteroidal anti-inflammatory drugs with the incidence of postmenopausal breast cancer for risk subgroups defined by selected nonmodifiable or difficult to modify breast cancer risk factors in order to better understand the potential risk-benefit ratio for targeted chemoprevention. Patients and MethodsPostmenopausal women with no history of cancer on July 1, 1992 (N=26,580), were prospectively followed up through December 31, 2005, for breast cancer incidence (N=1581). Risk subgroups were defined on the basis of family history of breast cancer, age at menarche, age at menopause, parity/age at first live birth, personal history of benign breast disease, and body mass index. Hazard ratios (HRs) and 95% CIs adjusted for other breast cancer risk factors were estimated using Cox models. ResultsAspirin use was associated with a lower incidence of breast cancer for women with a family history of breast cancer (HR, 0.62 for 6 or more times per week vs never use; 95% CI, 0.41-0.93) and those with a personal history of benign breast disease (HR, 0.69; 95% CI, 0.50-0.95) but not for women in higher-risk subgroups for age at menarche, age at menopause, parity/age at first live birth, or body mass index. In contrast, inverse associations with aspirin use were observed in all lower-risk subgroups. Nonsteroidal anti-inflammatory drug use had no association with breast cancer incidence. ConclusionOn the basis of their increased risk of breast cancer, postmenopausal women with a family history of breast cancer or a personal history of benign breast disease could potentially be targeted for aspirin chemoprevention studies. Future studies are needed to confirm these findings.

Abstract A43: Population attributable risk of postmenopausal breast cancer according to known and modifiable breast cancer risk factors

Abstract Introduction: Multiple risk factors for postmenopausal breast cancer are well established. We aimed to determine the proportion of breast cancers in the population that are attributable to established risk factors, and to different combinations of risk factors, to better understand the proportion of breast cancer which could be prevented by changes in modifiable risk factors. Methods: We used data from the Nurses' Health Study (NHS), an ongoing prospective study of 121,700 US nurses initiated in 1976. Information on breast cancer risk factors and breast cancer diagnosis is collected every two years through mailed questionnaires. Follow-up for this cohort of women through 2008 has been greater than 90%. The analysis was restricted to postmenopausal women. Relative risks and their 95% confidence intervals were estimated by Cox models stratified by calendar year and age in months at the time of each questionnaire return using the counting process data structure to facilitate the incorporation of time-varying covariates. We included the following established breast cancer risk factors in the analyses: age, age at menarche, height, age at first birth/parity, current adult BMI/weight change since age 18, alcohol consumption, physical activity, breast feeding, menopausal hormone therapy, family history of breast cancer, and prior benign breast disease. Full and partial population attributable risk percents (PARs) were calculated. We conducted analyses for total invasive breast cancer, estrogen receptor (ER)+, and ER- breast cancer. Results: Over the course of follow-up, 8,421 postmenopausal invasive breast cancer cases developed over 2,424,778 person years between 1980 and 2008. As expected, earlier age at menarche, increasing weight gain since age 18, increasing alcohol consumption, current use of menopausal hormones, and being tall were all significantly positively associated with risk of breast cancer in multivariate models. Because age has a large influence on the risk of breast cancer we estimated the PAR both with and without age. When all of the risk factor variables except for age were include in the model the PAR for all invasive breast cancers was 0.62 (95% CI 0.46-0.75). Thus, if women could change to the lowest risk category for all of the variables considered, the number of invasive breast cancers would be reduced by 62%. In models that additionally included age, the PAR was 0.92 (95%CI 0.76-0.97) for total invasive and 0.95 (95%CI 0.75-0.99) for ER+ breast cancer and 0.86 (95%CI 0.21-0.98) for ER- breast cancer. However, because many of the risk factors considered are not easily modifiable, we also examined more readily modifiable risk factors singly and in combinations. The risk factor with the largest PAR, was BMI/weight gain since age 18 (PAR=0.24(95%CI 0.13-0.34)). Reproductive risk factors such as age at first birth/parity (PAR=0.10 (95%CI 0.07-0.14)) and age at menarche (PAR=0.08 (95%CI 0.03-0.12)) also had modest impact on the PAR, both of which were higher for ER+ breast cancer than ER- breast cancer. When considering all of the modifiable risk factors together we found that changing one's risk factor profile to have the lowest weight gain, no alcohol consumption, high physical activity, breast feeding and no hormone use was associated with a PAR of 0.38 (95%CI 0.23-0.52) for overall invasive breast cancer. Conclusion: The established breast cancer risk factors explain a large proportion of both ER+ and ER- postmenopausal breast cancers in the population. The most important modifiable risk factor for postmenopausal breast cancer prevention is maintaining a healthy weight. Citation Format: Rulla M. Tamimi, Molin Wang, Mathew Pazzaris, Stephanie A. Smith-Warner, Walter C. Willett, A. Heather Eliassen, Donna Spiegelman, David J. Hunter. Population attributable risk of postmenopausal breast cancer according to known and modifiable breast cancer risk factors. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A43.

Abstract B34: Breast cancer risk factors and screening practices among Hispanics subgroups in the United States

Abstract Hispanics are the fastest growing minority group in the United States (US). In the US, breast cancer (BC) is the most frequently diagnosed cancer among Hispanic women. Differences observed in BC risk by Hispanic origin may be due to variations in the exposure to known BC risk factors. However the heterogeneity of the prevalence of BC risk factors among Hispanic subgroups has not been characterized. We sought to assess differences in BC screening and the distribution of BC risk factors among US Hispanic women by subgroups using data from the 2012 National Health Interview Survey. We compared modifiable BC risk factors (body mass index, physical activity, alcohol use, and smoking) and BC screening (mammogram use) among Hispanic subgroups (Mexican American, South/Central American, Caribbean American, Other Hispanic) using multinomial logistic regression. After adjusting for several confounders, South/Central American women were less likely (OR=0.76; 95% CI: 0.57-1.02) and women from Other Hispanic origin were more likely (OR=1.49; 95% CI: 0.90-2.46) to be obese compared to Mexican Americans. Also, compared to Mexican Americans, women of Other Hispanic origin were more likely to be former and current smokers (OR=1.38; 95% CI: 0.77-3.56; OR=3.52; 95% CI: 2.03-6.11, respectively). Caribbean American women were 49% (OR=0.51; 95% CI: 0.35-0.74) less likely to meet the national guidelines for physical activity as compared to Mexican American women. Among women aged 40 years and older, Caribbean American women were 40% (OR=1.40; 95% CI: 1.07-1.83) more likely to have had a mammogram in the past 12 months as compared to Mexican Americans. These data demonstrate important breast cancer risk factor differences among Hispanic subgroups. The current findings will be useful for developing interventions targeted to reduce the burden of BC among Hispanic women. Citation Format: Mary Vanellys Diaz-Santana, Katherine W. Reeves. Breast cancer risk factors and screening practices among Hispanics subgroups in the United States. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B34.

Abstract CT111: Green tea extract supplementation, estrogen metabolism and breast cancer risk in postmenopausal women at high risk of breast cancer

Abstract Background: Green tea intake may be associated with reduced risk of several cancers including breast cancer. One of the proposed mechanisms by which green tea may modify breast cancer risk is through effects on estrogen metabolism. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of both estrogens and tea catechins, may also have a role. Few studies have examined the effects of green tea intake on circulating and urinary estrogens and estrogen metabolites, and even less is known about the potential modifying influence of polymorphisms in the COMT gene. Objectives: To investigate the effects of daily intake of a highly concentrated green tea extract (GTE) for one year on circulating and urinary estrogens and their metabolites in postmenopausal women with different COMT genotypes. Methods: The Minnesota Green Tea Trial (MGTT), a randomized, double-blind, placebo-controlled, phase II clinical trial, enrolled 1075 healthy postmenopausal women with heterogeneously or extremely dense breast tissue (age = 59.78 ± 5.02 years; body mass index = 25.70 ± 8.21 kg/m2). Participants were 93% non-Hispanic white and non-current hormone users. Half of the participants (n = 538) were randomly assigned to the GTE group and were given 4 capsules a day, each containing 200 mg epigallocatechin gallate (EGCG) and the others (n = 537) to the placebo group. Twenty-four hour urine samples were collected at month 0 and at the end of the study, and fasting blood samples were drawn at months 0, 6 and 12. Circulating and urinary estrogens, as well as urinary estrogen metabolites were quantified by liquid chromatography-tandem mass spectrometry. Results: GTE supplementation was associated with reduced urinary estriol (-10.7%, P = 0.08) and 2-methoxy estrone (-12.2%, P = 0.014) compared with baseline, and these changes were significantly greater than the corresponding changes in the placebo group (P = 0.003, and P = 0.02, respectively). GTE supplementation had no significant effects on serum or urinary estrone and estradiol. Among women with the low activity COMT genotype, GTE supplementation reduced urinary estrone (-5.3%) compared with women with high activity COMT (+2.1%) (between groups comparison P = 0.049). Statistical analyses are ongoing to examine the potential modifying effects of COMT genotype on other urinary estrogen metabolites. Conclusion: Daily intake of high-dose green tea extract for 12 months exerts significant effects on urinary excretion of estrogen metabolites, and these effects may be modified by COMT polymorphisms. The potential beneficial effects of green tea extract on estrogen metabolism support the further development of green tea as a potential chemopreventive agents for estrogen-related disease prevention. Funding source: NIH/NCI (R01 CA127236). Citation Format: Hamed Samavat, Renwei Wang, Anna Wu, Jian-Min Yuan, Mindy Kurzer. Green tea extract supplementation, estrogen metabolism and breast cancer risk in postmenopausal women at high risk of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT111. doi:10.1158/1538-7445.AM2015-CT111

Addressing barriers to uptake of breast cancer chemoprevention for patients and providers.

Breast cancer is the most common malignancy among women in the United States, and the primary prevention of this disease is a major public health issue. Because there are relatively few modifiable breast cancer risk factors, pharmacologic interventions with antiestrogens have the potential to significantly affect the primary prevention setting. Breast cancer chemoprevention with selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene, and with aromatase inhibitors (AIs) exemestane and anastrozole, is underutilized despite several randomized controlled trials demonstrating up to a 50% to 65% relative risk reduction in breast cancer incidence among women at high risk. An estimated 10 million women in the United States meet high-risk criteria for breast cancer and are potentially eligible for chemoprevention, but less than 5% of women at high risk who are offered antiestrogens for primary prevention agree to take it. Reasons for low chemoprevention uptake include lack of routine breast cancer risk assessment in primary care, inadequate time for counseling, insufficient knowledge about antiestrogens among patients and providers, and concerns about side effects. Interventions designed to increase chemoprevention uptake, such as decision aids and incorporating breast cancer risk assessment into clinical practice, have met with limited success. Clinicians can help women make informed decisions about chemoprevention by effectively communicating breast cancer risk and enhancing knowledge about the risks and benefits of antiestrogens. Widespread adoption of chemoprevention will require a major paradigm shift in clinical practice for primary care providers (PCPs). However, enhancing uptake and adherence to breast cancer chemoprevention holds promise for reducing the public health burden of this disease.

Abstract MS1-1: Characterising cancer risks for carriers of mutations in BRCA1, BRCA2, PALB2, and RAD51C genes

Abstract The presentation will provide an overview of the latest developments and challenges in understanding the penetrance of mutations in the BRCA1, BRCA2, PALB2 and RAD51C genes. Genetic counselling currently relies on average cancer risk estimates obtained from retrospective penetrance studies involving large numbers of families segregating mutations in these genes. The talk will present penetrance estimates from ongoing prospective analyses, based on data from the International BRCA1/2 Carrier Cohort Study, the largest cohort of BRCA1/2 mutation carriers worldwide that includes >10,000 mutation carriers at baseline with prospective follow-up information. Several common alleles and other risk factors have now been shown to modify breast cancer risk for BRCA1 and BRCA2 mutation carriers. The talk will review the latest efforts and results from the Consortium of Investigators of Modifiers of BRCA1/2 to identify genetic modifiers of risk and provide individualised cancer risks for BRCA1 and BRCA2 mutation carriers on the basis of polygenic risk scores. We will also present penetrance estimates based on analyses of combined data from families segregating mutations in PALB2 and RAD51C, the largest efforts of their kind. Finally the presentation will demonstrate how the effects of common and rare breast cancer susceptibility variants are incorporated into the BOADICEA model to provide comprehensive risks of developing breast cancer in the future. Citation Format: Antonis C. Antoniou. Characterising cancer risks for carriers of mutations in BRCA1, BRCA2, PALB2, and RAD51C genes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr MS1-1.

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

IntroductionIndividuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.MethodsWe genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.ResultsWe discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.ConclusionsThis study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0567-2) contains supplementary material, which is available to authorized users.

In Utero exposure to low-dose alcohol induces reprogramming of mammary development and tumor risk in MMTV-erbB-2 transgenic mice.

There is increasing evidence that prenatal exposure to environmental factors may modify breast cancer risk later in life. This study aimed to investigate the effects of in utero exposure to low-dose alcohol on mammary development and tumor risk. Pregnant MMTV-erbB-2 mice were exposed to alcohol (6 g/kg/day) between day 13 and day 19 of gestation, and the female offspring were examined for tumor risk. Whole mount analysis indicated that in utero exposure to low-dose alcohol induced significant increases in ductal extension at 10 weeks of age. Molecular analysis showed that in utero alcohol exposure induced upregulation of ERα signaling and activation of Akt and Erk1/2 in pubertal mammary glands. However, enhanced signaling in the EGFR/erbB-2 pathway appeared to be more prominent in 10-week-old glands than did signaling in the other pathways. Interestingly, tumor development in mice with in utero exposure to low-dose alcohol was slightly delayed compared to control mice, but tumor multiplicity was increased. The results indicate that in utero exposure to low-dose alcohol induces the reprogramming of mammary development by mechanisms that include altered signaling in the estrogen receptor (ER) and erbB-2 pathways. The intriguing tumor development pattern might be related to alcohol dose and exposure conditions, and warrants further investigation.

BREAST CANCER RISK EVALUATION - A CORRELATION BETWEEN MAMMOGRAPHIC DENSITY AND THE GAIL MODEL

Background: The Gail model is a statistical tool, which assesses breast cancer probability, based on nonmodifiable risk factors. In contrast, the evaluation of mammographic breast density is an independent and dynamic risk factor influenced by interventions modifying breast cancer risk incidence. Objective: The aim of the present study is to compare the possibilities for risk factor integration and analysis and to search for a correlation between mammographic density and the Gail model for breast cancer risk evaluation. Materials and Methods: The subject of this prospective study is a cohort of 107 women at ages from 37 to 71 years, who have had benign breast diseases, digital mammograms, and Gail model risk evaluation. Mammographic density is evaluated in craniocaudal projection subjectively visually and objectively using the computer imaging software. (Image J software) The Gail risk evaluation is completed using the standardized NCI questionnaire (Breast Cancer Risk Assessment Tool). Results: In concordance with the Breast Imaging Reporting and Data System (BI-RAD) by ACR, mammographic density is evaluated using a four-grade scale. Low density D1 (less than 25%) was determined in 24 cases, D2 (25-50%) in 36 cases, D3 (51-75%) in 31 cases and high density D4 (greater than 75%) in 16 cases. According to the Gail model, 80 (74,8%) of the examined patients did not have an increased risk (less than 1,67% for a five-year period), whereas the remaining 27 (25,2%) had a statistically significant increase in risk (greater than 1,67% for a five-year period). Women with increased risk more often present with denser breast (34% with D3, D4 versus 18,3% for D1, D2). Conclusion: The Gail model does not adequately explain the correlation between breast density and statistically calculated risk. The development of more detailed tools, which take into consideration breast density, as well as other risk factors, may be helpful for a more accurate evaluation of the individual risk for breast cancer.

A genetic variant at 12p11 significantly modifies breast cancer risk in a genetically homogenous island population.

Genome-wide association studies have identified novel breast cancer susceptibility loci at 12q24 (rs1292011), 12p11 (rs10771399) and 21q21 (rs2823093). The aim of our study was to investigate the prevalence of variants at these three loci in an Irish sample, and to examine the association between these variants and breast cancer in this cohort. DNA was extracted from the blood or buccal swabs of Irish patients with breast cancer (cases), as well as from healthy Irish female controls. Genotyping was performed for each target using a Taqman-based platform. Data were analysed using IBM Statistical Package for the Social Sciences version 22. Genotyping was performed on samples from 1,267 patients with breast cancer and 841 cancer-free controls. The per-allele odds ratio associated with the minor allele at 12p11 was found to be 0.67 (0.54-0.81, p < 0.001). Genotype-specific odds ratios showed an allele dosage effect with odds ratio of 0.76 (0.6-0.95) for heterozygotes, and 0.23 (0.1-0.51) for rare homozygotes. Minor allele frequencies of the variants at 12q24 and 21q21 did not differ significantly between cases or controls. All three investigated variants were identified in the Irish population. The polymorphism rs10771399 was strongly associated with breast cancer risk in this cohort, and was shown to be associated with reduced odds ratio for all molecular subtypes.

Abstract A09: In utero exposure to estrogen promotes mammary tumor risk in MMTV-erbB-2 transgenic mice through induction of ER-erbB-2 crosstalk

Abstract The mammary gland during in utero stage is in a largely undifferentiated state, which is particularly vulnerable to environmental factors. Increasing evidence indicates that intrauterine hormonal and nutritional alterations may significantly modify breast cancer risk later in life. A well-known case is the “DES Daughter” story. However, the underlying mechanisms are largely unknown and more prenatal risk factors remain to be identified. Therefore, development of sensitive and reliable model systems to identify those factors with mechanistic insight is of great significance in breast cancer prevention. Previously, most studies on in utero exposure-modulated breast cancer risk used carcinogenic models. While this system is valuable in providing proof of concept, due to challenges in elucidating molecular pathways induced by in utero exposures and by carcinogens, molecular mechanistic studies in these models are compromised. In this study, we aimed to establish an animal model for studying in utero exposure to environmental hormones-induced mammary tumor risk using MMTV-erbB-2 transgenic mice. erbB-2 is an oncogene that is amplified in ~25-30% of human breast cancer. The MMTV-erbB-2 mice have a defined genetic background and tumor development patterns, which is of advantage in mechanistic studies. When pregnant MMTV-erbB-2 mice were injected with 20 ng/mouse/day of Estradiol (E2) between day 13 and day 19 of gestation, mammary tumor development of the offspring was significantly accelerated, as compared to control. The average tumor latencies of the control and the E2 group were 36 and 32 weeks respectively. In utero exposure to E2 also induced earlier vaginal opening and prolonged length of estrous stages. Whole mount analysis indicated that in utero exposure to E2 increased mammary epithelial density at 6 and 10 weeks of age. Importantly, we also found that in utero exposure to E2 induced a concurrent upregulation of signaling in estrogen receptor α (ER α) and receptor tyrosine kinase pathways in the mammary tissues, as indicated by increased expression of ER target genes (c-myc, cyclin D1, EGFR, and Bcl-2) and phosphorylation of EGFR, erbB-2, Akt1 and Erk1/2. Use of gefitinib also, a small molecular inhibitor of EGFR, abrogated the upregulation of both pathways in mammary tissues with in utero exposure to E2, suggesting a role of EGFR in in utero exposure to E2 induced crosstalk between the two pathways. Our data indicates that in utero exposure to E2 induces a systematic pro-estrogenic effect and enhanced signaling and crosstalk between ER and EGFR/erbB-2 pathways. Deregulation of the two critical pathways in the premalignant tissues is associated with mammary tumor risk later in life. This will lead to further mechanistic studies, such as in utero exposure to hormones, induced epigenetic regulation, and reprogramming. This model system may represent a model for studying gene-environment interaction in breast carcinogenesis and can be used to study the effects of in utero exposure to other environmental and dietary factors modulated breast cancer risk. Citation Format: Zhikun Ma, Amanda Blackwelder, Xiaohe Yang. In utero exposure to estrogen promotes mammary tumor risk in MMTV-erbB-2 transgenic mice through induction of ER-erbB-2 crosstalk. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A09.

Breast cancer prevention knowledge, beliefs, and information sources between non-Hispanic and Hispanic college women for risk reduction focus.

Although growing research focuses on breast cancer screenings, little is known about breast cancer prevention with risk reduction awareness for ethnic differences among college-age women. This study examined breast cancer prevention knowledge, beliefs, and information sources between non-Hispanic and Hispanic college women. Using a cross-sectional study, women at a university in the Southwest completed a 51-item survey about breast cancer risk factors, beliefs, and media and interpersonal information sources. The study was guided by McGuire's Input Output Persuasion Model. Of the 546 participants, non-Hispanic college women (n=277) and Hispanic college women (n=269) reported similar basic knowledge levels of modifiable breast cancer risk factors for alcohol consumption (52%), obesity (72%), childbearing after age 35 (63%), and menopausal hormone therapy (68%) using bivariate analyses. Most common information sources were Internet (75%), magazines (69%), provider (76%) and friends (61%). Least common sources were radio (44%), newspapers (34%), and mothers (36%). Non-Hispanic college women with breast cancer family history were more likely to receive information from providers, friends, and mothers. Hispanic college women with a breast cancer family history were more likely to receive information from their mothers. Breast cancer prevention education for college women is needed to include risk reduction for modifiable health behavior changes as a new focus. Health professionals may target college women with more information sources including the Internet or apps.

Breast cancer risk, nightwork, and circadian clock gene polymorphisms.

Night shift work has been associated with an increased risk of breast cancer pointing to a role of circadian disruption. We investigated the role of circadian clock gene polymorphisms and their interaction with nightwork in breast cancer risk in a population-based case-control study in France including 1126 breast cancer cases and 1174 controls. We estimated breast cancer risk associated with each of the 577 single nucleotide polymorphisms (SNPs) in 23 circadian clock genes. We also used a gene- and pathway-based approach to investigate the overall effect on breast cancer of circadian clock gene variants that might not be detected in analyses based on individual SNPs. Interactions with nightwork were tested at the SNP, gene, and pathway levels. We found that two SNPs in RORA (rs1482057 and rs12914272) were associated with breast cancer in the whole sample and among postmenopausal women. In this subpopulation, we also reported an association with rs11932595 in CLOCK, and with CLOCK, RORA, and NPAS2 in the analyses at the gene level. Breast cancer risk in postmenopausal women was also associated with overall genetic variation in the circadian gene pathway (P=0.04), but this association was not detected in premenopausal women. There was some evidence of an interaction between PER1 and nightwork in breast cancer in the whole sample (P=0.024), although the effect was not statistically significant after correcting for multiple testing (P=0.452). Our results support the hypothesis that circadian clock gene variants modulate breast cancer risk.

Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility.

Compared to the well-defined anti-apoptotic role of myeloid cell leukemia sequence 1 (MCL1), its antiproliferative function in tumorigenesis is less studied. We had recently reported that regulatory variants of MCL1 contribute to enhanced promoter activity but reduced risk of lung cancer. We hypothesized that MCL1 expression may manifest antiproliferative phenotype and its functional variations may have etiological relevance for breast cancer. We manipulated MCL1 expression in MCF-7 cells and MDA231 with overexpression and knockdown, analyzed the effects on cell viability and cell cycling phase, and characterized the correlation with expression profiles of key regulators of cell cycle. We further genotyped the -190 insertion polymorphism and the neighboring single nucleotide polymorphisms (SNPs) in 745 breast cancer patients and 537 controls and analyzed their association with cancer risk. We confirmed that heightened expression of MCL1 resulted in decreased proliferation ability of breast cancer cells. We further observed that MCL1 overexpression in breast cancer cells resulted in cell cycle progression arresting in S phase and concomitant enhanced expression of p27, which could be rescued by p27 knockdown with co-transfection of small interfering RNA (siRNA). Furthermore, we found a significant reduction in breast cancer risk [odds ratio (OR) = 0.74; 95 % confidence interval (CI) = 0.59-0.93] associated with -190 insertion genotype; the expression-enhancing regulatory haplotype (OR 0.79; 95 % CI 0.66-0.95) and diplotype (OR 0.71; 95 % CI 0.57-0.89) were consistently associated with decreased cancer susceptibility. The study demonstrates that the expression-enhancing regulatory variants of MCL1 are protective modifiers of breast cancer risk, and reduced cell proliferation and arrested cell cycle progression partly mediated by p27 might be the underlying mechanism.

Associations between anthropometric characteristics, physical activity, and breast cancer risk in a Canadian cohort.

Obesity, physical inactivity, and sedentary behavior, concomitants of the modern environment, are potentially modifiable breast cancer risk factors. This study investigated the association of anthropometric measurements, physical activity and sedentary behavior, with the risk of incident, invasive breast cancer using a prospective cohort of women enrolled in the Canadian Study of Diet, Lifestyle and Health. Using a case-cohort design, an age-stratified subcohort of 3,320 women was created from 39,532 female participants who returned completed self-administered lifestyle and dietary questionnaires at baseline. A total of 1,097 incident breast cancer cases were identified from the entire cohort via linkage to the Canadian Cancer Registry. Cox regression models, modified to account for the case-cohort design, were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between anthropometric characteristics, physical activity, and the risk of breast cancer. Weight gain as an adult was positively associated with risk of post-menopausal breast cancer, with a 6% increase in risk for every 5kg gained since age 20 (HR 1.06; 95% CI 1.01-1.11). Women who exercised more than 30.9 metabolic equivalent task (MET) hours per week had a 21% decreased risk of breast cancer compared to women who exercised less than 3 MET hours per week (HR 0.79; 95% CI 0.62-1.00), most evident in pre-menopausal women (HR 0.62; 95% CI 0.43-0.90). As obesity reaches epidemic proportions and sedentary lifestyles have become more prevalent in modern populations, programs targeting adult weight gain and promoting physical activity may be beneficial with respect to reducing breast cancer morbidity.

High prevalence ofGPRC5Agermline mutations inBRCA1-mutant breast cancer patients

In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutation c.183delG [p. Arg61fs] in an orphan G protein-coupled receptor GPRC5A. An extended case-control study revealed a tenfold enrichment for this mutation in BC patients carrying the 5382insC allele of BRCA1, the major founder mutation in the Russian population, compared to wild-type BRCA1 BC cases [6/117 (5.1%) vs. 8/1578 (0.5%), p = 0.0002]. In mammary tumors (n = 60), the mRNA expression of GPRC5A significantly correlated with that of BRCA1 (p = 0.00018). In addition, the amount of GPRC5A transcript was significantly lower in BC obtained from BRCA1 mutation carriers (n = 17) compared to noncarriers (n = 93) (p = 0.026). Accordingly, a siRNA-mediated knockdown of either BRCA1 or GPRC5A in the MDA-MB-231 human BC cell line reduced expression of GPRC5A or BRCA1, respectively. Knockdown of GPRC5A also attenuated radiation-induced BRCA1- and RAD51-containing nuclear DNA repair foci. Taken together, these data suggest that GPRC5A is a modifier of BC risk in BRCA1 mutation carriers and reveals a functional interaction of these genes.