Bone A Fertile Soil For The Breast Cancer Seed

The mineralized matrix of the bone is a rich store of growth factors and calcium that are released during bone resorption (5). The released growth factors contribute to the growth of breast cancer cells in bone (6). Insulinlike growth factors (IGFs) I and II and transforming growth factor p (TGFP) are the most abundant growth factors in bone (5). A role of bone matrix IGF I and II in bone metastasis has not been completely demonstrated. Currently, only TGFp has been shown to be actively released from the bone matrix by osteoclast resorption (7). Expression of a dominant negative TGFp receptor subunit in MDA-MB-231 breast cancer cells blocked responsiveness to TGFp and decreased bone metastases in mice (8). TGFp inhibitors are effective in preclinical models to block bone metastases (9-12).

Actions of the two main bone cell types are coupled. The bone-forming osteoblast and the bone-resorbing osteoclast maintain bone homeostasis by a process of remodeling (13). Osteoclasts resorb bone, leaving a pit within which osteoblasts then form new bone (13). Osteoclast formation is regulated by cells of the osteoblast lineage that express macrophage-colony stimulating factor (M-CSF) and receptor activator of NFkappaB ligand (RANKL) (14). M-CSF induces monocyte/macrophage cell precursors to express the receptor activator of NFkappaB (RANK) (14). Binding of RANKL to RANK stimulates the differentiation of the precursor cells into osteoclasts and increases osteoclast activation and survival (14). Imbalances in the activities of osteoblasts and osteoclasts can lead to increased bone loss or bone formation. Breast cancer cells in bone cause such imbalances, producing predominantly osteolytic (bone destructive), but also osteoblastic (bone forming) and mixed bone lesions (14).

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