Role of PTH Receptor in Breast Cancer Metastasis to Bone

摘要

Breast cancer metastasizes to bone more frequently than any other tumor hut the mechanisms responsible remain unclear. Parathyroid hormone-related protein (PTRrP) is an established tumor product which produces hypercalcemia by stimulating osteoclastic bone resorption. Recently, a role for PTHrP in the establishment of breast cancer metastases in bone has been proposed. PTHrP acts via the common parathyroid hormone/PTHrP receptor (PTHR), which has been demonstrated in breast cancer cell lines and metastatic breast tumors. These findings suggest that an autocrine and/or paracrine loop between PTHrP and its receptor is involved in the establishment of breast cancer metastases in bone. The proposed work will test the hypothesis that an autocrine/paracrine loop between PTHrP and the PTHR is involved in the establishment of breast cancer metastases in bone. Enhancement of this loop, by either increasing receptor expression, constitutive activation of the receptor or by TGF beta stimulation, should increase the metastasis formation. Conversely, interruption of this loop, by overexpression of a signaling-deficient receptor, should reduce metastasis. Breast cancer lines will be produced which stably express wild-type, constitutively active or signaling- deficient PTHR. Cell lines will be characterized in vitro for growth and PTHrP production and in vivo for the development of bone metastases. The first year of this three-year award has resulted in significant training and research accomplishments in (1) laboratory molecular biology techniques as well construction of stable cell lines which will facilitate the study of breast cancer metastases to bone; (2) data analysis and public presentation skills; (3) mechanisms of cancer metastases with respect to bone metastases. My research accomplishments have exceeded the original statement of work in that I have accomplished that proposed for year one in addition to studies which determine.