Abstract
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.
Highlights
SEPTEMBER 5, 2008 VOLUME 283 NUMBER 36 face receptor (GPCR) that binds calcium ions and allows cells to react to changes in the extracellular calcium concentration (Ca2ϩo) [1]
We found that changes in intracellular cAMP, but not phospholipase C or MAPK signaling, correlated with the opposing effects of the calcium-sensing receptor (CaR) on Parathyroid hormone-related protein (PTHrP) production
Base-line PTHrP secretion was similar in mammary epithelial cells (MMECs) and Comma-D cells, increasing doses of calcium or treatment with calcimimetics led to a progressive increase in PTHrP secretion in the Comma-D cells (Fig. 1B)
Summary
SEPTEMBER 5, 2008 VOLUME 283 NUMBER 36 face receptor (GPCR) that binds calcium ions and allows cells to react to changes in the extracellular calcium concentration (Ca2ϩo) [1]. Activation of ERK1 and -2 through a PLC, intracellular calcium transient, protein kinase C (PKC) pathway has been suggested to be important for CaR-mediated suppression of PTH secretion in dispersed parathyroid cells [16, 18, 19]. Astrocytes, osteoblasts, cytotrophoblasts, ovarian surface epithelial cells, and HEK 293 cells transfected with the CaR all secrete more PTHrP in response to increased Ca2ϩo or treatment with calcimimetics [29]. Likewise, in malignancies such as human prostate cancer, human breast cancer, and rat Leydig cell tumor cell lines, CaR signaling increases PTHrP production [29]. Negative regulation of PTHrP in response to calcium delivery appears to be an important component of an endocrine feedback circuit between the lactating breast and bone, which acts to maintain a steady flow of skeletal calcium for milk production [33, 34]
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