Calcium-sensing receptor and breast cancer

Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, but it is not known how PTHrP is upregulated during breast tumorigenesis. Here we report a central role in this process for CaSR, a calcium-sensing receptor which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo. Tissue-specific disruption of the CaSR gene in mammary epithelial cells in MMTV-PymT mice inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. These antiproliferative effects appeared to be mediated by nuclear actions of PTHrP that decreased p27kip1 levels and prevented nuclear accumulation of the pro-apoptotic factor AIF. Taken together, our findings suggest CaSR-PTHrP interactions as a locus for the development of therapeutic agents to limit metastasis to bone and other microenvironments where elevated PTHrP and extracellular calcium have been causally implicated.

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