Genetic regulation of the estrogen receptor and inherited predisposition to breast cancer

For many families severely affected with breast cancer, no inherited causal allele has been detected in any tumor suppressor gene. In an effort to understand the genetics underlying breast cancer in these families, we evaluated 136 such families for coinheritance of breast cancer with each of 79 common variants reported as high-confidence "risk alleles" for breast cancer by meta-analyses of genome-wide association studies. Simulations based on allele frequencies and family structures revealed one (and only one) of these 79 variants to cosegregate with breast cancer in the families significantly more frequently than expected by chance. This variant (rs2046210) is located 180 kb proximal to <i>ESR1</i>, encoding the estrogen receptor alpha. Reporter assays in MCF7 cells revealed enhancement by the genomic segment at this site of activity of <i>ESR1</i> promoters, but no difference in effect among alternative haplotypes. In contrast, the 600 kb genomic region including <i>ESR1</i> and rs2046210 harbored 11 rare variants, each of which cosegregated with breast cancer in one or a few families. For 9 of these 11 variants, reporter assays indicated significant allele-specific effects on <i>ESR1</i> promoters, with the breast-cancer-linked allele of each variant yielding higher promoter activity. At the site with the most striking effect, the breast-cancer-linked allele was associated with increased binding by transcription factor AP2-gamma TFAP2C in both MCF7 and T47D cells. These results demonstrate coinheritance with breast cancer of rare alleles that increase activity of <i>ESR1</i> promoters, and suggest that rare <i>ESR1</i> regulatory alleles may contribute to inherited predisposition to breast cancer.