Breast cancer is the second leading cause of cancer-related deaths among women in the United States, and most of these deaths are due to metastasis to a secondary site, which is primarily the skeleton. The connection between primary breast cancer and frequent bone metastasis is poorly understood. Here, I investigate the role of two features of the bone microenvironment that may help elucidate this connection, the presence of mineral and mechanical stimuli. Bone marrow-derived mesenchymal stem cells (BM-MSCs) cultured with tumor-secreted soluble factors from bone-specific metastatic breast cancer cells deposited more mineral relative to factors from primary and lung-specific breast cancer cells, which could potentially explain the source of microcalcifications in the primary breast tumor. Additionally, I developed an in vitro loading system utilizing a mineralized 3-D model of the bone microenvironment. In the absence of loading, BM-MSCs in hydroxyapatite-containing (HA) scaffolds demonstrated enhanced osteoblastic activity compared to those in non-mineral containing control scaffolds. Under compressive loading, BM-MSCs cultured with tumor secreted soluble factors exhibited early commitment to the osteoblastic lineage. Loading did not affect breast cancer cell viability in this system, but expression of Runx2, a regulator of secretion of osteolytic proteins, was decreased 35% with loading. Taken together, these results suggest that bone marrow-derived stem cells are the source of microcalcifications, and metastatic tumor cells may affect the ‘vicious cycle’ by modulating the activity of osteoblasts and osteoclasts.