Abstract 3821: Epigenetic mechanisms in early-onset hereditary cancer: Insights from a new Brca1 mouse model
Authors: Carman Li, Alyssa Cordes, Michael U. Oliphant, S. Aidan Quinn, Mayura Thomas, Laura M. Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P. Gupta, Shailja Pathania, Aviv Regev, Cigall Kadoch, Senthil K. Muthuswamy, Joan S. Brugge
Journal: Cancer Research (2025)

Abstract Germline mutations in the BRCA1 gene increase the lifetime risk of breast cancer to as high as 80%. Preventive measures and early detection strategies remain limited, largely due to an incomplete understanding of the molecular mechanisms underlying cancer predisposition in these high-risk individuals. Here, using newly developed genetically engineered mouse models (GEMMs), we directly demonstrate for the first time that this early disease onset in germline mutation carriers cannot be fully explained by the conventional "two-hit" hypothesis (i.e., the shorter time required to inactivate one versus two alleles in heterozygous germline mutation carriers versus non-carriers), and we provide evidence suggesting an additional epigenetic mechanism for this disease predisposition. Specifically, when Brca1-heterozygous and wild-type GEMMs are both induced to Brca1 nullizygosity simultaneously, the two cohorts do not follow the prediction of the two-hit hypothesis to develop tumors at a similar rate. Instead, the heterozygous mice still form tumors significantly earlier than the wild-type mice, suggesting the existence of inherent aberrations in the Brca1-heterozygous state that can accelerate cancer formation independent of the two-hit explanation. Further investigation reveals a previously unappreciated epigenetic effect of Brca1 gene haploinsufficiency. Single-cell RNA-seq and ATAC-seq analyses uncover a unique chromatin accessibility profile in ostensibly normal Brca1-heterozygous mammary alveolar cells (the tumor cell-of-origin) that is distinct from wild-type cells and partially mimics the chromatin and RNA-level changes in fully transformed tumor cells. These altered chromatin regions are enriched for the ELF5 and AP-1 transcription factor binding sites, and in vivo experiments reveal critical roles of these factors in regulating tumorigenesis. Finally, analyses of downstream target genes identify Wnt10a as a key driver of tumorigenesis through activating the WNT pathway, and functional experiment demonstrates that Wnt10a activation is sufficient to accelerate tumor formation and advance disease progression. These findings support a model in which Brca1 heterozygosity accelerates cancer development via tumor-like chromatin changes that prime the expression of specific cancer-promoting genes. Our work sheds light on a hitherto unknown epigenetic mechanism for tumor predisposition in BRCA1 hereditary breast cancer. These findings suggest new opportunities for early interception and have broad potential implications in other hereditary cancers with different tissue and gene specificity. Citation Format: Carman Li, Alyssa Cordes, Michael U. Oliphant, S. Aidan Quinn, Mayura Thomas, Laura M. Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P. Gupta, Shailja Pathania, Aviv Regev, Cigall Kadoch, Senthil K. Muthuswamy, Joan S. Brugge. Epigenetic mechanisms in early-onset hereditary cancer: Insights from a new Brca1 mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3821.