The
calcium-sensing receptor (CaR) is a
G-protein-coupled receptor that signals in response to extracellular
calcium and regulates
parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of
parathyroid hormone-related protein (
PTHrP) and participate in the regulation of
calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to stimulate
PTHrP production by
breast cancer cells. In this study, we confirmed that the CaR inhibits
PTHrP production by MMECs but stimulates
PTHrP production by Comma-D cells (immortalized murine mammary cells) and MCF-7 human
breast cancer cells. We found that changes in intracellular cAMP, but not
phospholipase C or MAPK signaling, correlated with the opposing effects of the CaR on
PTHrP production. Pharmacologic stimulation of cAMP accumulation increased
PTHrP production by normal and transformed breast cells. Inhibition of
protein kinase A activity mimicked the effects of CaR activation on inhibiting
PTHrP secretion by MMECs and blocked the effects of the CaR on stimulating
PTHrP production in Comma-D and MCF-7 cells. We found that the CaR coupled to Galphai in MMECs but coupled to Galphas in Comma-D and MCF-7 cells. Thus, the opposing effects of the CaR on
PTHrP production are because of alternate
G-protein coupling of the receptor in normal versus transformed breast cells. Because
PTHrP contributes to
hypercalcemia and bone
metastases, switching of
G-protein usage by the CaR may contribute to the pathogenesis of
breast cancer.