Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer

Carman Man-Chung Li; Alyssa Cordes; Michael U J Oliphant; S Aidan Quinn; Mayura Thomas; Laura M Selfors; Francesca Silvestri; Nomeda Girnius; Gianmarco Rinaldi; Jason J Zoeller; Hana Shapiro; Christina Tsiobikas; Kushali P Gupta; Shailja Pathania; Aviv Regev; Cigall Kadoch; Senthil K Muthuswamy; Joan S Brugge

doi:10.1038/s41588-024-01958-6

Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer

Nat Genet. 2024 Nov 11. doi: 10.1038/s41588-024-01958-6. Online ahead of print.

Authors

Carman Man-Chung Li¹, Alyssa Cordes², Michael U J Oliphant², S Aidan Quinn^{3

4}, Mayura Thomas², Laura M Selfors², Francesca Silvestri², Nomeda Girnius², Gianmarco Rinaldi², Jason J Zoeller², Hana Shapiro², Christina Tsiobikas², Kushali P Gupta², Shailja Pathania^{5

6}, Aviv Regev^{7

8}, Cigall Kadoch^{3

4}, Senthil K Muthuswamy^{9

10}, Joan S Brugge^{11

12}

Affiliations

¹ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. carman_li@hms.harvard.edu.
² Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
³ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Department of Biology, University of Massachusetts Boston, Boston, MA, USA.
⁷ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Genentech, South San Francisco, CA, USA.
⁹ Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
¹⁰ Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Department of Cell Biology, Harvard Medical School, Boston, MA, USA. joan_brugge@hms.harvard.edu.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA. joan_brugge@hms.harvard.edu.

PMID: 39528827
DOI: 10.1038/s41588-024-01958-6

Abstract

Germline BRCA1 mutation 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 Brca1 heterozygosity, we demonstrate that early tumor onset in a Brca1 heterozygous background cannot be fully explained by the conventional 'two-hit' hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1 heterozygous 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 Brca1 heterozygous 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 Wnt10a as strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1 haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies.