The Role of Parathyroid Hormone-Related Protein in Breast Cancer Mediated Osteolysis.
Annual rept. 30 Sep 96-29 Sep 97,
TEXAS UNIV HEALTH SCIENCE CENTER AT SANANTONIO
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This proposal is designed to investigate the role of PTHrP in breast cancer-mediated osteolysis. Observations in patient with bone metastases suggest that breast cancer cells in bone express PTHrP more frequently than in soft tissue site of metastasis or in the primary tumor. Three isoforms of PTHrP, 1-139, 1-141 and 1-173, are products of alternative splicing in humans, but the specific contribution of each of these isoforms to osteolytic metastasis caused by breast cancer as not been evaluated. To determine the role of these isoforms in breast cancer metastasis to bone, the human breast cancer cell line MDA-MB-231 MDA-231 was stably transfected with similar amounts of cDNAs for human prepro PTHrP 1-139, -1-141 or -1-173, driven by a CMV promoter, and studied in a model of human breast cancer metastasis one. Conditioned media from stable MDAIPTHrP-I-139 clones contained significantly more PTHrP, compared with DNPTHrP-1-141, -1-173 or parental MDA-231. Nude mice were inoculated into the left cardiac ventricle with MDA 31 PTHrP-1-139, -1-141, -1-173 clones or parental MDA-231 cells. Osteolytic lesion area of radiographs wa greatest in mice bearing MDAIPTHrP-1-139 compared with those bearing MDAIPTHrP-1-141, -1-173 or parenta DA-231. Cawas significantly higher in the MDAIPTHrP-1-139 compared with the MDAIPTHrP-1-141, -1-1730 arental MDA-231 groups as was the plasma PTHrP concentration. The data demonstrate that overexpression of PTHrP 1-139 isoform in the human breast cancer cell line MDA-MB-231 results in greater PTHrP secretion in vitro an enhanced osteolysis with increased plasma PTHrP concentrations and hypercalcemia in vivo compared wit overexpression of PTHrP-1-141 or -1-173. Differential cell processing of the isoforms may result in more efficient secretion of PTHrP-1-139 and the osteolysis that is characteristic of b
- Anatomy and Physiology
- Medicine and Medical Research