Alterations in the preneoplastic breast microenvironment of BRCA1/2 mutation carriers revealed by spatial transcriptomics.

Breast 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 the and genes are significant risk factors for specific subtypes of breast cancer. mutations are associated with basal-like breast cancers, whereas mutations are associated with luminal-like disease. There are currently few chemoprevention strategies available for / mutation 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 from / mutation 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 in -deficient mammary epithelial cells differs from -deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of / mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in / -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 in and mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.