Parathyroid hormone‐related protein (PTH‐rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH‐rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH‐rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH‐rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH‐rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor‐β (TGF‐β), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH‐rP expression and tumor cell growth. To investigate the role of PTH‐rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA‐MB‐231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH‐rP secretion was altered, 2) the effects of PTH‐rP were neutralized, or 3) the responsiveness to TGF‐β was abolished in MDA‐MB‐231 cells. Cultured MDA‐MB‐231 cells secreted low amounts of PTH‐rP that increased fivefold in response to TGF‐β. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH‐rP was overexpressed in the tumor cells, bone metastases were increased. MDA‐MB‐231 cells transfected with the cDNA for human preproPTH‐rP secreted a tenfold greater amount of PTH‐rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH‐rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH‐rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA‐MB‐231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH‐rP by the MDA‐MB‐231 cells in vitro. The role of bone‐derived TGF‐β in the development and progression of bone metastasis was studied by transfecting MDA‐MB‐231 cells with a cDNA encoding a TGF‐β type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF‐β. Stable clones expressing this mutant receptor (MDA/TβRIIΔcyt) did not increase PTH‐rP secretion in response to TGF‐β stimulation compared with controls of untransfected MDA‐MB‐231 or those transfected with the empty vector. Mice inoculated into the left cardiac ventricle with MDA/TβRIIΔcyt had fewer and smaller bone metastases as assessed radiographically and histomorphometrically compared with controls. Taken together, these data suggest that PTH‐rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF‐β responsiveness of breast carcinoma cells may be important for the expression of PTH‐rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be …