Mammographic density (MD) and mutations in BRCA1 (BRCA1 MT) are two strong risk factors for breast cancer. Clarifying the molecular basis of the cancer risk in these highrisk women and identifying biomarkers to identify women who would benefit from closer surveillance and chemoprevention, and validating molecular pathways towards which approved therapies exist is clinically important. We found that the extracellular matrix (ECM) in women with high MD and those with BRCA1 MTs is stiffer and that a stiff ECM sensitizes mammary epithelial cells (MECs) to progesterone to induce more receptor activator of NF kappa B ligand (RANKL). RANK stimulates breast cell growth, expands stem cells, and induces inflammation and breast cancer metastasis. We detected more RANKL in the breasts of women with high MD, and data suggest RANK receptors are higher in breast tissue from women with BRCA1 MTs who have more breast stem cells and develop triple negative breast cancer (TNBC). Studies also suggest RANK activity may be higher in African American (AA) women who often develop TNBCs. Thus, we predict that risk to malignancy in women with high MD is fostered by a stiff ECM because it sensitives the epithelium to progesterone to increase RANK signaling that drives breast cell growth and tissue inflammation and expands breast stem cell frequency. This phenotype could also explain the predilection to develop TNBCs in other high-risk women with BRCA1 MTs and AA women who prior studies suggest may have higher RANK signaling. We will test this by: 1) Determining in mouse models if tissue mechanics drives mammary gland transformation and metastasis by enhancing Rank signaling and driving cell growth and inflammation and stem cell expansion. 2) Exploring associations and causality between Rank, inflammation and stem cell frequency and ECM stiffness in breast tissue from women at high risk for cancer and those who develop TNBCs, and in breast tissue from BRCA1 MT women treated with the RANKL inhibitor Denosumab. 3) Determining how ECM stiffness sensitives MECs to progesterone, and if the breast tissue in women at higher risk to malignancy or TNBCs are intrinsically sensitive to progesterone or RANKL. The studies will: 1) Identify RANK signaling as a biomarker for breast cancer risk and TNBCs and will provide evidence to support chemoprevention trials using RANKL inhibitors. 3) Provide a biological basis for the increased risk conferred by MD, 4) Clarify mechanisms whereby BRCA1 MTs increase breast cancer and provide biomarkers to stratify risk in this population. 5) Obtain insight into the biological basis of the aggressive TNBC breast cancers in AA women.