Abstract
The calcium-sensing receptor (CaSR) is expressed in normal breast epithelial cells and in breast cancer cells. During lactation, activation of the CaSR in mammary epithelial cells increases calcium transport into milk and inhibits parathyroid hormone-related protein (PTHrP) secretion into milk and into the circulation. The ability to sense changes in extracellular calcium allows the lactating breast to actively participate in the regulation of systemic calcium and bone metabolism, and to coordinate calcium usage with calcium availability during milk production. Interestingly, as compared to normal breast cells, in breast cancer cells, the regulation of PTHrP secretion by the CaSR becomes rewired due to a switch in its G-protein usage such that activation of the CaSR increases instead of decreases PTHrP production. In normal cells the CaSR couples to Gαi to inhibit cAMP and PTHrP production, whereas in breast cancer cells, it couples to Gαs to stimulate cAMP and PTHrP production. Activation of the CaSR on breast cancer cells regulates breast cancer cell proliferation, death and migration, in part, by stimulating PTHrP production. In this article, we discuss the biology of the CaSR in the normal breast and in breast cancer, and review recent findings suggesting that the CaSR activates a nuclear pathway of PTHrP action that stimulates cellular proliferation and inhibits cell death, helping cancer cells adapt to elevated extracellular calcium levels. Understanding the diverse actions mediated by the CaSR may help us better understand lactation physiology, breast cancer progression and osteolytic bone metastases.
Highlights
The extracellular calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that was first identified because of its ability to regulate parathyroid hormone (PTH) secretion in response to changes in extracellular free calcium (Ca2+) (Brown et al, 1993; Brown, 2013)
These findings clearly suggest that the CaSR affects breast cancer cell proliferation and apoptosis, at least in part, by stimulating the production of parathyroid hormone-related protein (PTHrP), which, in turn, acts in the nucleus to regulate p27kip1 and apoptosis-inducing factor (AIF) levels
Our findings suggest that CaSR signaling can increase intracrine/nuclear signaling by PTHrP and directly stimulate tumor cell proliferation and enhance the ability of the cells to survive in the face of the elevated extracellular calcium concentrations resulting from active bone resorption (Figure 3)
Summary
The extracellular calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that was first identified because of its ability to regulate parathyroid hormone (PTH) secretion in response to changes in extracellular free calcium (Ca2+) (Brown et al, 1993; Brown, 2013). While this did not affect secretory differentiation of the epithelial cells, it did have consequences for calcium transport, PTHrP production and systemic calcium metabolism during lactation, confirming previous pharmacologic and genetic studies (VanHouten et al, 2004, 2007; Ardeshirpour et al, 2006; Mamillapalli et al, 2013) These studies suggest that, despite its effects on proliferation and apoptosis in breast cancer cells (see below), the CaSR does not have a dominant role in regulating morphological development or differentiation in the normal mammary gland. Elevated levels of phosphocholine and total choline-containing compounds have been observed in almost every cancer type studied and may be associated with tumor progression (Glunde et al, 2011) In the aggregate, these data support that notion that the CaSR promotes increased proliferation of breast cancer cells and suggest two interesting signaling pathways that may mediate these effects. Ongoing studies are attempting to define the molecular mechanisms that underlie the G-protein switching that occurs in response to malignant transformation
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