Brca1haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer

Germline BRCA1mutation carriers face a high breast cancer risk; however, the underlying mechanisms for this risk are not completely understood. Using a new genetically engineered mouse model of germline Brca1heterozygosity, we demonstrate that early tumor onset in a Brca1heterozygous background cannot be fully explained by the conventional ‘two-hit’ hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1heterozygous state. Single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells. Transcription factor analyses identify loss of ELF5 and gain of AP-1 sites in these epigenetically primed regions; in vivo experiments further implicate AP-1 and Wnt10aas strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies.