Mechanisms of Breast Cancer-Induced Osteolysis

To determine if some malignant cells serve an accessory function and promote osteoclast differentiation, we cultured T47D human breast cancer cells with murine osteoclast precursors. We find bone resorbing osteoclasts develop with 7-10 days and do so in a cancer cell-dependent manner. Establishing osteoclast recruitment is not a universal property of all breast cancers. We have isolated T47D subclones incapable of osteoclastogenesis. Thus, formation of osteoclasts in the presence of breast cancer cells requires contact between the two cell types. We also find that MDA-MD-231 human breast cancer cells selected for preferential adherence to bone marrow stroma, when injected intracardiac into nude mice, produce 6 times as many osteolytic metastases as their stroma non-adherent counterparts. Despite their preferential metastases to skeleton, bone resorbing tumor cells derived from the stroma-adherent in comparison to the non-adherent parental cells express lower levels of alpha v beta 3 integrin. While lower alpha v beta 3 expressing MDA-231 cells preferentially home to bone, the high integrin containing cells selectively metastasize to lungs. Thus, alpha v beta 3 expression represents a marker of site-selective metastasis by a human breast cancer cell line.