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Cancer Res. 2016 Sep 15;76(18):5348-60. doi: 10.1158/0008-5472.CAN-15-2614. Epub 2016 Jul 22.

Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone-Related Protein.

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Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.
Cancer Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii School of Medicine, Honolulu, Hawaii.
Section of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Endocrine Unit, San Francisco and Veteran Affairs Medical Center, University of California, San Francisco, California.
Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven Connecticut.


Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth, and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, 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 reduced tumor PTHrP expression and 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. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27(kip1) levels and prevented nuclear accumulation of the proapoptotic factor apoptosis inducing factor. Taken together, our findings suggest that CaSR-PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression. Cancer Res; 76(18); 5348-60.

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