Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, however, the underlying mechanisms are poorly understood. Runx2, a bone-specific transcriptional factor, is abnormally expressed in highly metastatic breast cancer cells. Here, we found that TSSC1 inhibits breast cancer cell invasion. Subsequently, TSSC1 is confirmed as a target of Runx2 and is negatively ... [Show full abstract] regulated by Runx2. Furthermore, overexpression of Runx2 induces bone osteolysisin a TSSC1-dependent manner. Our results may provide a strategy for the treatment of breast cancer and the prevention of skeletal metastasis.