Estrogen interactions with breast cancer risk variants in regulatory DNA
Year: 2026
Type: preprint
Abstract: Insight into population-level gene-environment (GxE) interactions is a major goal in understanding polygenic diseases, such as breast cancer. We integrated massively parallel reporter assays (MPRA), chromatin profiling, and network analysis to identify estrogen-responsive breast cancer variants. Screening 1,604 GWAS-identified breast cancer variants identified 73 estrogen-modulated SNVs (emSNVs). Chromatin accessibility modeling validated allele-specific effects, identifying variants that disrupt pioneer factor binding to chromatin and others that modulate transcription factor (TF) recruitment to pre-accessible enhancers. emSNV targets converged on pathways including mitochondrial metabolism, NF-κB signaling, and chromatin regulation. Aggregating emSNVs into a polygenic risk score (PRS E2 ) revealed interactions with reproductive risk factors in 13,026 post-menopausal BRCA cases and 108,265 controls, including age at first birth (p=0.0052); a control PRS lacking estrogen-responsive variants showed no interactions. This framework bridges molecular and epidemiological GxE studies to uncover variants whose disease associations depend on environmental context, with implications for understanding polygenic disease risk.
Source: medRxiv
Authors: Ibtihal Elfaki, Laura N. Kellman, Robin M. Meyers, Luca Ducoli, Martina Fu, Kamal Obbad, Smarajit Mondal, Xue Yang, Douglas F. Porter, David L. Reynolds, Suhas Srinivasan, Taishi Nakase, Mineto Ota, Tania Fabo, Jordan M Meyers, Lu Yang, Nasa Sinnot-Armstrong, Kenneth E. Westerman, Linda Kachuri, Paul A. Khavari
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7212401754