Effects of secretory products of breast cancer cells on osteoblast-like cells.

The pathogenesis of breast cancer-induced osteolysis remains largely unknown. To evaluate the potential role of osteoblasts as target cells during this process, we incubated SaOS-2 human osteoblast-like cells (OBL) with culture media conditioned by proliferative (PM, 'Proliferation Media') or confluent (CfM, 'Confluence Media') MCF-7 human breast cancer cells. CfM decreased the growth of OBL by 26% (P < 0.01) while PM was without significant effect on this parameter. In contrast, both PM and CfM obtained from MCF-7 cultures increased the cyclic AMP (cAMP) response of OBL to the osteolytic agents PTH (10(-8) M) and PTH-related peptide (PTHrP, 10(-8) M) by a factor of about 3 (P < 0.001), and to prostaglandin E(2) (PGE(2),10(-6) M) by a factor of about 2 (P < 0.01). No significant modulation of OBL growth or sensitivity to PTH, PTHrP, or PGE2 was induced by media obtained from HBL-100 non-malignant immortalized breast epithelial cell cultures. 17betaestradiol (E(2), 10(-8) M) and the antiestrogen tamoxifen (Tam, 10(-7) M) added for 48 h to MCF-7 cultures before collecting conditioned media attenuated and potentiated, respectively, the PM- but not the CfM-induced increase in the response of OBL to PTH or PTHrP Along the same line, the addition to MCF-7 conditioned media of a polyclonal anti-transforming growth factor-beta (TGF-beta) antibody attenuated by about 25% (P < 0.01) the PM-induced increase in OBL response to PTH and PTHrP while abrogating the modulatory effects of E(2) and Tam on that response. Together, our results indicate that MCF-7 breast cancer cells secrete factors which inhibit the growth of OBL and increase their sensitivity to various osteolytic agents. TGF-beta was only partly responsible for these effects, and accounts for their modulation by E(2) and Tam. The identification of other osteoblast-modulatory factor(s) should contribute to a better understanding and treatment of breast cancer-induced osteolysis.