Alterations in the preneoplastic breast microenvironment ofBRCA1/2mutation carriers revealed by spatial transcriptomics

Abstract

AbstractBreast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in theBRCA1andBRCA2genes are significant risk factors for specific subtypes of breast cancer.BRCA1mutations are associated with basal-like breast cancers, whereasBRCA2mutations are associated with luminal-like disease. There are currently few chemoprevention strategies available forBRCA1/2mutation carriers, and irreversible prophylactic mastectomy is the primary option. Designing chemo-preventive strategies requires an in-depth understanding of the physiological processes underlying tumor initiation. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues fromBRCA1/2mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling inBRCA2-deficient mammary epithelial cells differs fromBRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues ofBRCA1/2mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated inBRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. These results reveal alterations in the communication between mammary epithelial cells and the microenvironment inBRCA1andBRCA2mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.