Estrogen alters breast cancer risk variants in human DNA
Screening 1,604 variants identified 73 estrogen-responsive variants that interacted with age at first birth in 13,026 post-menopausal breast cancer cases and 108,265 controls.
medRxiv
In a study combining human functional genomics with records from 13,026 post-menopausal breast cancer cases and 108,265 controls, researchers identified gene-environment interactions driven by estrogen. The team screened 1,604 genome-wide association study variants using massively parallel reporter assays, chromatin profiling, and network analysis. The screen revealed 73 estrogen-modulated single-nucleotide variants. Chromatin accessibility modeling indicated that these variants disrupt pioneer factor binding or alter transcription factor recruitment to pre-accessible enhancers. Targets of these variants converged on pathways governing mitochondrial metabolism, NF-κB signaling, and chromatin regulation. An aggregated polygenic risk score based on these variants interacted with reproductive factors, including age at first birth (p=0.0052), whereas a control score without estrogen-responsive variants showed no interactions.
Why it matters
Hormone exposures shift across the female lifespan and menopause, and mapping estrogen-responsive variants helps explain how lifetime endocrine history alters post-menopausal cancer susceptibility.
Caveats
This study is a preprint and has not yet been peer-reviewed. The clinical associations rely on observational epidemiological data in post-menopausal cohorts.
The paper
Estrogen interactions with breast cancer risk variants in regulatory DNA
Show 16 more authors
Luca Ducoli, Martina Fu, Kamal Obbad, Smarajit Mondal, Xue Yang, Douglas F. Porter, David L. Reynolds, Suhas Srinivasan, Taishi C. Nakase, Mineto Ota, Tania Fabo, Jordan M. Meyers, Lu Yang, Nasa Sinnott-Armstrong, Kenneth E. Westerman, Linda Kachuri,Stanford Medicine · VA Palo Alto Health Care System
medRxiv · 11 Sep 2026 · Preprint, not peer-reviewed
