FABP7 Progenitors are a Targetable Metabolic Root in the BRCA1 Breast

It has been nearly 3 decades since the discovery of the BRCA1/2 genes and their link to breast cancer risk, with prophylactic mastectomy remaining the primary management option for these high-risk mutation carriers. The current paucity of interception strategies is due to undefined, targetable cancer precursor populations in the high-risk breast. Despite known cellular alterations in the BRCA1 breast, epithelial populations at the root of unwarranted cell state transitions remain unresolved. Here, we identify a root progenitor population that is dysregulated in BRCA1 carriers stemming from the metabolic role of BRCA1. This fatty-acid binding protein 7 (FABP7) expressing luminal progenitor population is spatially confined to the mammary ducts, has enhanced clonogenic capacity, and is the predicted origin of mixed basal-luminal differentiation in the BRCA1 but not BRCA2 breast. We show global H3K27 acetylation is reduced within ductal FABP7 cells in BRCA1 carriers in situ, linking to a non-canonical metabolic role of BRCA1 in regulating acetyl-CoA pools and de novo fatty acid synthesis. We demonstrate FABP7 progenitor capacity is preferentially ablated in BRCA1 carriers through inhibition of fatty acid metabolism using an FDA-approved fatty acid synthase (FASN) inhibitor. This study lays the foundation for metabolic control of breast progenitor dynamics to mitigate breast cancer risk in the BRCA1 breast. Overall design: Single-cell RNA sequencing of primary human breast samples from prophylactic mastectomies in non-carrier, BRCA1 mutation, and BRCA2 mutation carriers, using Multiplexed using lipid-tagged indices (MULTI-seq). Samples were staged for menstrual cycle.