Breast cancer screening and early stage diagnosis is typically performed by X-ray mammography, which detects microcalcifications. Despite being one of the most reliable features of nonpalpable breast cancer, the processes by which these microcalcifications form are understudied and largely unknown. In the current work, we have investigated the genetic drivers for the formation of microcalcifications in breast cancer cell lines, and have investigated their involvement in disease progression. We have shown that stable silencing of the Osteopontin (OPN) gene decreased the formation of hydroxyapatite in MDA-MB-231 breast cancer cells in response to osteogenic cocktail. In addition, OPN silencing reduced breast cancer cell migration. Furthermore, breast cancer cells that had spontaneously metastasized to the lungs in a mouse model of breast cancer had largely elevated OPN levels, while circulating tumor cells in the same mouse model contained intermediately increased OPN levels as compared to parental cells. The observed dual roles of the OPN gene reveal the existence of a direct relationship between calcium deposition and the ability of breast cancer cells to metastasize to distant organs, mediated by common genetic factors.