Variants of estrogen-related genes and breast cancer risk in European and African American women.

It has been observed previously that compared with women of European ancestry (EA), those of African ancestry (AA) are more likely to develop estrogen receptor (ER)-negative breast cancer, although the mechanisms have not been elucidated. We tested the associations between breast cancer risk and a targeted set of 20 genes known to be involved in estrogen synthesis, metabolism, and response and potential gene-environment interactions using data and samples from 1307 EA (658 cases) and 1365 AA (621 cases) participants from the Women's Circle of Health Study (WCHS). Multivariable logistic regression found evidence of associations with single-nucleotide polymorphisms (SNPs) in the ESR1 gene in EA women (rs1801132, odds ratio (OR)=1.47, 95% CI=1.20-1.80, P=0.0002; rs2046210, OR=1.24, 95% CI=1.04-1.47, P=0.02; and rs3020314, OR=1.43, 95% CI=1.19-1.70, P=0.00009), but not in AA women. The only other gene associated with breast cancer risk was CYP1A2 in AA women (rs2470893, OR=1.42, 95% CI=1.00-2.02, P=0.05), but not in EA women. When stratified by ER status, ESR1 rs1801132, rs2046210, and rs3020314 showed stronger associations in ER-positive than in ER-negative breast cancer in only EA women. Associations with the ESR1 SNPs in EA women also appeared to be stronger with longer endogenous estrogen exposure or hormonal replacement therapy use. Our results indicate that there may be differential genetic influences on breast cancer risk in EA compared with AA women and that these differences may be modified by tumor subtype and estrogen exposures. Future studies with a larger sample size may determine the full contribution of estrogen-related genes to racial/ethnic differences in breast cancer.

[1]  Jane E. Carpenter,et al.  Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. , 2014, Carcinogenesis.

[2]  S. Yao,et al.  Associations between Estrogen Receptor–Negative Breast Cancer and Timing of Reproductive Events Differ between African American and European American Women , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[3]  S. Yao,et al.  Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry , 2014, International journal of cancer.

[4]  S. Cole,et al.  Replication of breast cancer susceptibility loci in whites and African Americans using a Bayesian approach. , 2014, American journal of epidemiology.

[5]  J. Loud.  Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers , 2014, Breast Cancer Research and Treatment.

[6]  S. Yao,et al.  Parity and breastfeeding among African-American women: differential effects on breast cancer risk by estrogen receptor status in the Women’s Circle of Health Study , 2013, Cancer Causes & Control.

[7]  C. Ambrosone,et al.  Rethinking sources of representative controls for the conduct of case–control studies in minority populations , 2013, BMC Medical Research Methodology.

[8]  Wei Zheng,et al.  Evaluating Genome-Wide Association Study-Identified Breast Cancer Risk Variants in African-American Women , 2013, PloS one.

[9]  Jaana M. Hartikainen,et al.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk , 2013, Nature Genetics.

[10]  Y. Shang,et al.  Estrogen and cancer. , 2013, Annual review of physiology.

[11]  C. Rotimi,et al.  Genetic Susceptibility Loci for Subtypes of Breast Cancer in an African American Population , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[12]  N. de Klerk,et al.  Participation in population-based case-control studies: does the observed decline vary by socio-economic status? , 2012, Paediatric and perinatal epidemiology.

[13]  C. Carlson,et al.  Estrogen-related genes and their contribution to racial differences in breast cancer risk , 2012, Cancer Causes & Control.

[14]  R. Hoover,et al.  Estrogen metabolism and risk of breast cancer in postmenopausal women. , 2012, Journal of the National Cancer Institute.

[15]  S. Yao,et al.  Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case-control study , 2012, Breast Cancer Research.

[16]  Gary K. Chen,et al.  Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans. , 2011, Human molecular genetics.

[17]  I. Thompson,et al.  Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate Cancer Prevention Trial. , 2011, Carcinogenesis.

[18]  D. Germain.  Estrogen carcinogenesis in breast cancer. , 2011, Endocrinology and metabolism clinics of North America.

[19]  Peter Kraft,et al.  Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. , 2011, Journal of the National Cancer Institute.

[20]  J. Palmer,et al.  Parity and Lactation in Relation to Estrogen Receptor Negative Breast Cancer in African American Women , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[21]  C. Carty,et al.  Replication of Breast Cancer GWAS Susceptibility Loci in the Women's Health Initiative African American SHARe Study , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[22]  Xiaofeng Zhu,et al.  The landscape of recombination in African Americans , 2011, Nature.

[23]  David Reich,et al.  Validation of a small set of ancestral informative markers for control of population admixture in African Americans. , 2011, American journal of epidemiology.

[24]  Clement Adebamowo,et al.  Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus , 2010, PLoS genetics.

[25]  C. Haiman,et al.  Exploring genetic susceptibility to cancer in diverse populations. , 2010, Current opinion in genetics & development.

[26]  Hongbing Shen,et al.  Potentially functional polymorphisms in ESR1 and breast cancer risk: a meta-analysis , 2010, Breast Cancer Research and Treatment.

[27]  H. Valdimarsdottir,et al.  Conducting Molecular Epidemiological Research in the Age of HIPAA: A Multi-Institutional Case-Control Study of Breast Cancer in African-American and European-American Women , 2009, Journal of oncology.

[28]  J. Long,et al.  Evaluation of 11 Breast Cancer Susceptibility Loci in African-American Women , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[29]  C. Perou,et al.  Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  S. Land,et al.  African American-preponderant single nucleotide polymorphisms (SNPs) and risk of breast cancer. , 2009, Cancer epidemiology.

[31]  Julian Peto,et al.  Association of ESR1 gene tagging SNPs with breast cancer risk. , 2009, Human molecular genetics.

[32]  J. Haines,et al.  Genome-wide association study identifies a novel breast cancer susceptibility locus at 6q25.1 , 2009, Nature Genetics.

[33]  M. Beckmann,et al.  Association of ESR 1 gene tagging SNPs with breast cancer risk , 2009 .

[34]  Jarvis T. Chen,et al.  Race/ethnicity and breast cancer estrogen receptor status: impact of class, missing data, and modeling assumptions , 2008, Cancer Causes & Control.

[35]  L. Carey,et al.  Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer. , 2008, Oncology reports.

[36]  M. Khoury,et al.  A navigator for human genome epidemiology , 2008, Nature Genetics.

[37]  C. Perou,et al.  Epidemiology of basal-like breast cancer , 2008, Breast Cancer Research and Treatment.

[38]  Chava Kimchi-Sarfaty,et al.  Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. , 2007, Cancer research.

[39]  A. Howell,et al.  Origins of breast cancer subtypes and therapeutic implications , 2007, Nature Clinical Practice Oncology.

[40]  D. Allred,et al.  The estrogen paradox , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[41]  T. Rebbeck,et al.  Pairwise Combinations of Estrogen Metabolism Genotypes in Postmenopausal Breast Cancer Etiology , 2007, Cancer Epidemiology Biomarkers & Prevention.

[42]  D. Altshuler,et al.  A systematic assessment of common genetic variation in CYP11A and risk of breast cancer. , 2006, Cancer research.

[43]  B. Zhu,et al.  Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding. , 2006, Endocrinology.

[44]  C. Ambrosone,et al.  Breast cancer in African-American women: differences in tumor biology from European-American women. , 2006, Cancer research.

[45]  François Vaillant,et al.  Steroid hormone receptor status of mouse mammary stem cells. , 2006, Journal of the National Cancer Institute.

[46]  J. Yager,et al.  Estrogen carcinogenesis in breast cancer. , 2006, The New England journal of medicine.

[47]  Zhao Chen,et al.  Ethnicity and breast cancer: factors influencing differences in incidence and outcome. , 2005, Journal of the National Cancer Institute.

[48]  S. Hankinson,et al.  Racial Differences in Premenopausal Endogenous Hormones , 2005, Cancer Epidemiology Biomarkers & Prevention.

[49]  L. Newman,et al.  Breast cancer in sub‐Saharan Africa: How does it relate to breast cancer in African‐American women? , 2005, Cancer.

[50]  C. Benz,et al.  Risk factors for estrogen receptor-positive breast cancer. , 2005, Archives of surgery.

[51]  S. Narum,et al.  Beyond Bonferroni: Less conservative analyses for conservation genetics , 2005, Conservation Genetics.

[52]  M. García-Closas,et al.  Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. , 2004, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[53]  S. Fuqua,et al.  Molecular aspects of estrogen receptor variants in breast cancer , 1995, Breast Cancer Research and Treatment.

[54]  N. Boyd,et al.  Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study , 2004, Breast Cancer Research.

[55]  Y. Miyoshi,et al.  Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women. , 2003, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[56]  A. Ellis.  Breast , 2002, BMJ : British Medical Journal.

[57]  T. Key,et al.  Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. , 2002, Journal of the National Cancer Institute.

[58]  G. Giles,et al.  CYP17 promoter polymorphism and breast cancer in Australian women under age forty years. , 2000, Journal of the National Cancer Institute.

[59]  P. Donnelly,et al.  Association mapping in structured populations. , 2000, American journal of human genetics.

[60]  R. Weinshilboum,et al.  Chapter 6: Estrogen Metabolism by Conjugation , 2000 .

[61]  C. Ambrosone,et al.  Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. , 2000, Journal of the National Cancer Institute. Monographs.

[62]  R. Weinshilboum,et al.  Estrogen metabolism by conjugation. , 2000, Journal of the National Cancer Institute. Monographs.

[63]  M. Gentile,et al.  Association between CYP17 gene polymorphism and risk of breast cancer in young women , 1999, International journal of cancer.

[64]  M. Pike,et al.  Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. , 1998, Cancer research.

[65]  G. Coetzee,et al.  A polymorphism in the CYP17 gene increases the risk of breast cancer. , 1997, Cancer research.

[66]  J. Madans,et al.  Use of postmenopausal hormone replacement therapy: estimates from a nationally representative cohort study. , 1997, American journal of epidemiology.

[67]  J. Liehr,et al.  Dual role of oestrogens as hormones and pro-carcinogens: tumour initiation by metabolic activation of oestrogens. , 1997, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[68]  N. Gordon.  Association of education and income with estrogen receptor status in primary breast cancer. , 1995, American journal of epidemiology.

[69]  E. Taioli,et al.  A CYP1A1 restriction fragment length polymorphism is associated with breast cancer in African-American women. , 1995, Cancer research.

[70]  M. Pike,et al.  Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. , 1993, Epidemiologic reviews.

[71]  C. Gutt,et al.  [Steroid hormone receptor status of colorectal cancers]. , 1990, Onkologie.

[72]  L. Luzzatto.  Interactions between Genetic Red‐Cell Defects and the Environment , 1975 .