Data from Spatial Transcriptomics Suggests That Alterations Occur in the Preneoplastic Breast Microenvironment of <i>BRCA1</i>/<i>2</i> Mutation Carriers

Abstract

<div>Abstract<p>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 <i>BRCA1</i> and <i>BRCA2</i> genes are significant risk factors for specific subtypes of breast cancer. <i>BRCA1</i> mutations are associated with basal-like breast cancers, whereas <i>BRCA2</i> mutations are associated with luminal-like disease. Defects in mammary epithelial cell differentiation have been previously recognized in germline <i>BRCA1</i>/<i>2</i> mutation carriers even before cancer incidence. However, the underlying mechanism is largely unknown. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from <i>BRCA1</i>/<i>2</i> mutation carriers and normal breast tissues from noncarrier 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 <i>BRCA2</i>-deficient mammary epithelial cells may differ from <i>BRCA1</i>-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of <i>BRCA1</i>/<i>2</i> mutation carriers is greater than in control tissues. More integrin–ligand pairs were differentially correlated in <i>BRCA1</i>/<i>2</i>-mutant breast tissues than noncarrier breast tissues with more integrin receptor-expressing stromal cells.</p>Implications:<p>These results suggest alterations in the communication between mammary epithelial cells and the microenvironment in <i>BRCA1</i> and <i>BRCA2</i> mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.</p></div>