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Breast cancer risk for carriers of  BRCA1  pathological variants is modified by genetic factors. Genetic variation in  HMMR  may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood. Here, we depict an interplay of molecular, cellular, and tissue microenvironment alterations that increase  BRCA1 -associated breast cancer risk. Analysis of genome-wide association results suggests that diverse biological processes, including links to  BRCA1 - HMMR  profiles, influence risk. HMMR overexpression in mouse mammary epithelium increases  Brca1 -mutant tumorigenesis by modulating the cancer cell phenotype and tumor microenvironment. Elevated HMMR activates AURKA and reduces ARPC2 localization in the mitotic cell cortex, which is correlated with micronucleation and activation of cGAS-STING and non-canonical NF-κB signaling. The initial tumorigenic events are genomic instability, epithelial-to-mesenchymal transition, and tissue infiltration of tumor-associated macrophages. The findings reveal a biological foundation for increased risk of  BRCA1 -associated breast cancer.

Modification of BRCA1-associated breast cancer risk by HMMR overexpression