The Role of the Calcium-Sensing Receptor in the Development and Progression of Cancer

The calcium-sensing receptor (CaR) is responsive to changes in the extracellular Ca(2+) (Ca(2+)(o)) concentration. It is a member of the largest family of cell surface receptors, the G protein-coupled receptors, and it has been shown to be involved in Ca(2+)(o) homeostasis. Apart from its primary role in Ca(2+)(o) homeostasis, the CaR may be involved in phenomena that allow for the development of many types of benign or malignant tumors, from parathyroid adenomas to breast, prostate, and colon cancers. For example, whereas the CaR is expressed in both normal and malignant breast tissue, increased CaR levels have been reported in highly metastatic primary breast cancer cells and breast cancer cell lines, possibly contributing to their malignancy and associated alterations in their biological properties. In these settings the CaR exhibits oncogenic properties. Enhanced CaR expression and altered proliferation of prostate cancer cells in response to increased Ca(2+)(o) have also been described. In contrast, colon and parathyroid cancers often present with reduced or absent CaR expression, and activation of this receptor decreases cell proliferation, suggesting a role for the CaR as a tumor suppressor gene. Thus, the CaR may play an important role in the development of many types of neoplasia. Herein, we review the role of the CaR in various benign and malignant tumors in further detail, describing its contribution to parathyroid tumors, breast, prostate, and colon cancers, and we evaluate how pharmacological manipulations of this receptor may be of interest for the treatment of certain cancers in the future.