Abstract
IntroductionAndrogens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).MethodsThe underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships (blocks) across the gene were then identified, and haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts (5,603 breast cancer cases and 7,480 controls).ResultsWe found no association between any genetic variation (SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed.ConclusionAmong postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.
Highlights
Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast
Breast cancer cases were identified in each cohort by self-report with subsequent confirmation of the diagnosis from medical records or tumour registries and/or from linkage with population-based tumour registries
Thirty-two single nucleotide polymorphisms (SNPs) with minor allele frequency greater than 5% in any of the five ethnic groups or greater than 1% overall were selected from this resequencing as well as any SNP available in dbSNP to be used to select haplotype-tagging SNPs
Summary
Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Levels of testosterone, which is produced in the ovaries, adrenal gland, and peripherally in adipose tissue, either change little or decline slightly after menopause [49] In both pre- and postmenopausal women, circulating testosterone levels are associated with increased risk of breast cancer [10,11,12,13,14,15,16,17]. The 3' UTR (untranslated region) of the AR contains sequence elements that bind to proteins involved in regulation of mRNA stability. This and other sequence-specific characteristics of AR mRNA, including putative function of the repeats in exon 1, have recently been reviewed [35]. The AR is expressed in the normal breast, as well as in primary and metastatic breast cancer tumours, and both the expression and protein levels are correlated with tumour invasiveness [36]
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