Parathyroid hormone-related protein: Primary osteolytic factor produced by breast tumor cells in vitro?

Tumor cells in bone metastases are thought to induce bone resorption primarily by releasing paracrine factors. Parathyroid hormone related protein (PTHrp) has been proposed to mediate osteolytic activity of many tumors. PTHrp is produced by 40% to 60% of breast tumors and is elevated in the serum of up to 50% of patients with breast cancer metastases to bone. Most biologic processes in humans are heterogeneous in nature, so the purpose of this study was to investigate the hypothesis that paracrine factors other than PTHrp could mediate bone resorption by breast tumor cells. Serum-free conditioned medium (CM) was collected from five human breast tumor cell lines and tested for bone resorption-stimulating activity (BRSA) in mouse calvaria organ cultures. CM from all tumor cells studied produced significant bone resorption, comparable to that produced by 10 nM PTH. Small amounts of immunoreactive PTHrp (1.4-12.5 pM) were produced by all breast tumor cell lines. When tested in vitro, equivalent amounts of human PTHrp[1-36] did not produce significant bone resorption. Indomethacin (1 μM) significantly blocked BRSA by CM from all cell lines but did not decrease BRSA by PTHrp. In contrast PTHrp antibody (130 μg/ml) completely blocked BRSA by 1 nM PTHrp but did not modify BRSA by CM of breast tumor cells. The results of this study support the hypothesis that breast cancer cells release paracrine factors in vitro that stimulate bone resorption by a mechanism that is partially dependent on prostaglandin synthesis and at least in part different from that of PTHrp. These results suggest that breast tumor cells may produce osteolytic factors that are distinct from PTHrp and that may constitute a more significant portion of the osteolytic activity produced at sites of metastasis in bone, although additional in vivo studies are needed to test this hypothesis.