Breast Cancer Metastasis to Bone Affects Osteoblast Differentiation

摘要

Breast cancer fatally metastasizes to bone and activates osteoclasts, cells that resorb bone, resulting in the formation of osteolytic lesions. Certain drugs, bisphosphonates, slow the action of osteoclasts, however, the bone lesions are not repaired. The osteoblasts should be able to repair the lesions by synthesizing new bone matrix. Instead, these cells appear to be inactivated by breast cancer, and the lesions do not heal. The purpose of this proposal was to understand what happens to osteoblasts in the presence of breast cancer. We hypothesized that breast cancer cells prevent pre-osteoblasts from completely maturing to osteoblasts. Our goals were to examine the effects of breast cancer cells on osteoblast proliferation, differentiation, and mature function. Using an osteoblast cell line and metastatic breast cancer cells, we found that conditioned medium from breast cancer cells inhibited osteoblast differentiation, as demonstrated by an inhibition of alkaline phosphatase, bone sialoprotein, and osteocalcin mRNA expression, and an inhibition of mineralization. These effects were mediated through TGF-beta present in the conditioned medium. We also found that MDA-MB-231 conditioned medium altered osteoblast morphology, actin stress fiber formation, and presence of focal adhesion plaques. TGF-beta, PDGF, and IGFII, all present in the conditioned medium, caused these effects by signaling through PI3K and rac.