Estrogen-responsive variants interact with reproductive risk factors

In a preprint analyzing 13,026 post-menopausal breast cancer cases and 108,265 controls, researchers evaluated how estrogen interacts with genetic risk loci. The authors screened 1,604 breast cancer risk variants identified by genome-wide association studies using massively parallel reporter assays and chromatin profiling. The screen identified 73 estrogen-modulated single-nucleotide variants that target pathways including mitochondrial metabolism, NF-κB signaling, and chromatin regulation. Chromatin accessibility modeling indicated these variants alter pioneer factor binding to chromatin or transcription factor recruitment to enhancers. Aggregating the 73 variants into an estrogen-responsive polygenic risk score revealed interactions with reproductive risk factors in the post-menopausal cohort, including age at first birth (p=0.0052). A control polygenic risk score lacking estrogen-responsive variants showed no such interactions.