Alterations in the preneoplastic breast microenvironment of

Area of Science:

• Oncology
• Genetics
• Cell Biology

Background:

• Germline mutations in BRCA1 and BRCA2 genes are major risk factors for specific breast cancer subtypes.
• BRCA1 mutations link to basal-like breast cancer, while BRCA2 mutations associate with luminal-like disease.
• Limited chemoprevention options exist for BRCA1/2 mutation carriers, with prophylactic mastectomy being the primary intervention.

Approach:

• Spatial transcriptomics was used to analyze preneoplastic breast tissues from BRCA1/2 mutation carriers and control tissues.
• Investigated defects in mammary epithelial cell differentiation and microenvironmental alterations.
• Examined spatially defined receptor-ligand interactions for autocrine and paracrine signaling.

Key Points:

• β1-integrin-mediated autocrine signaling differs between BRCA1-deficient and BRCA2-deficient mammary epithelial cells.
• Epithelial-to-stromal paracrine signaling is elevated in BRCA1/2 mutation carriers compared to controls.
• BRCA1/2-mutant tissues show more differential integrin-ligand correlations and stromal cell expression.

Conclusions:

• Significant alterations in mammary epithelial cell and microenvironment communication exist in BRCA1/2 mutation carriers.
• These findings provide a foundation for novel breast cancer chemoprevention strategies targeting high-risk individuals.
• Understanding cell-cell signaling is crucial for advancing personalized breast cancer prevention.