TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development

Breast cancer frequently metastasizes to the skeleton, and the associated b one destruction is mediated by the osteoclast. Growth factors, including tr ansforming growth factor-beta (TGF-beta), released from bone matrix by the action of osteoclasts, may foster metastatic growth. Because TGF-beta inhib its growth of epithelial cells, and carcinoma cells are often defective in TGF-beta responses, any role of TGF-beta in metastasis is likely to be medi ated by effects on the surrounding normal tissue. However, we present evide nce that TGF-beta promotes breast cancer metastasis by acting directly on t he tumor cells. Expression of a dominant-negative mutant (T beta RII Delta cyt) of the TGF-beta type II receptor rendered the human breast cancer cell line MDA-MB-231 unresponsive to TGF-beta. In a murine model of bone metast ases, expression of T beta RII Delta cyt by MDA-MB-231 resulted in less bon e destruction, less tumor with fewer associated osteoclasts, and prolonged survival compared with controls. Reversal of the dominant-negative signalin g blockade by expression of a constitutively active TGF-beta type I recepto r in the breast cancer cells increased tumor production of parathyroid horm one-related protein (PTHrP), enhanced osteolytic bone metastasis, and decre ased survival. Transfection of MDA-MB-23 1 cells that expressed the dominan t-negative T beta RII Delta cyt with the cDNA for PTHrP resulted in constit utive tumor PTHrP production and accelerated bone metastases. These data de monstrate an important role for TGF-beta in the development of breast cance r metastasis to bone, via the TGF-beta receptor-mediated signaling pathway in tumor cells, and suggest that the bone destruction is mediated by PTHrP.