Role of Parathyroid Hormone-Related Protein in Breast Cancer Mediated Osteolysis

The purpose of this study is to define the role of PTHrP in the pathophysiology of breast cancer using animal models of breast cancer-mediated humoral hypercalcemia and osteolytic bone metastases. Our previous studies reported in the first 3 years of this proposal indicate that 50 of breast cancer cell lines tested secrete low, but significant amounts of PTHrP. Over-expression of PTHrP-1-141 in the human breast cancer cell line, MDA-MB-231, increased osteolytic metastasis in a mouse model of human breast cancer metastasis to bone. Furthermore, treating mice with a neutralizing antibody to PTHrP inhibited the development of new bone metastasis and the progression of established bone metastasis caused by MDA-MB-231, a human breast cancer cell line which makes low amounts of PTHrP. Finally, as reported last year, of all three known isoforms of PTHrP, 1-139, 1-141, and 1-173, PTHrP-1-139 was more efficiently secreted by breast cancer cells. This was associated with enhanced osteolysis. Since our previous studies used primarily one cell line, MDA-MB-231, we next focused our attention on the role of PTHrP in bone metastases caused by an estrogen receptor positive line, MCF-7. Using the nude mouse model of human breast cancer metastasis to bone, we established that MCF-7 cells cause insignificant bone metastases, while PTHrP-overexpressing MCF-7 cells avidly metastasized to bone, induced osteoclast formation and hypercalcemia which was associated with increased plasma PTHrP concentrations.