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

Autor: Li, Carman Man-Chung, Cordes, Alyssa, Oliphant, Michael U. J., Quinn, S. Aidan, Thomas, Mayura, Selfors, Laura M., Silvestri, Francesca, Girnius, Nomeda, Rinaldi, Gianmarco, Zoeller, Jason J., Shapiro, Hana, Tsiobikas, Christina, Gupta, Kushali P., Pathania, Shailja, Regev, Aviv, Kadoch, S. Cigall, Muthuswamy, Senthil K., Brugge, Joan S.
Zdroj: Nature Genetics; 20240101, Issue: Preprints p1-13, 13p
Abstrakt: 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.
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