Breast cancers frequently metastasize to the skeleton and cause bone destruction. Tumor cells secrete factors that stimulate osteoclasts. The consequent osteolytic resorption releases active factors from the bone matrix, in particular transforming growth factor-beta (TGF-beta). The released factors then stimulate tumor cell signaling, which causes breast cancer cells to make increased amounts of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), interleukin-11 (IL-11), and vascular endothelial growth factor (VEGF). Therefore, tumor cell-bone cell interactions cause a vicious cycle in which tumor cells stimulate bone cells to cause bone destruction. As a consequence, the local microenvironment is enriched with factors that fuel tumor growth in bone. Transforming growth factor-beta is of particular importance because it increases breast cancer production of PTHrP. Parathyroid hormone-related protein then stimulates osteoblasts to express RANK (receptor activator of nuclear factor kappa B) ligand, which in turns enhances osteoclast formation and activity. Breast cancer osteolytic metastasis can be interrupted at four points in the vicious cycle: by neutralizing PTHrP biologic activity, by blocking the TGF-beta signaling pathway in the tumor cells, by inhibiting PTHrP gene transcription, and by inhibiting bone resorption.