The calcium-sensing receptor regulates PTHrP production and calcium transport in the lactating mammary gland

Switching of G-protein Usage by the Calcium-sensing Receptor Reverses Its Effect on Parathyroid Hormone-related Protein Secretion in Normal Versus Malignant Breast Cells

“…Exposure of MMECs to increasing concentrations of extracellular calcium or to calcimimetics inhibited PTHrP gene expression and decreased the secretion of PTHrP into the media (11,32). In contrast, activation of the CaR in Comma-D or MCF-7 cells stimulated PTHrP gene expression and increased the secretion of PTHrP into the media.…”

“…Normally, PTHrP is produced by the lactating breast, is secreted into the circulation, and stimulates osteoclastic bone resorption to liberate calcium from the maternal skeleton (32)(33)(34). Calcium, in turn, interacts with the CaR on mammary epithelial cells to inhibit PTHrP gene expression and secretion, thus defining a classic negative feedback loop that helps to maintain the delivery of calcium to the breast to be used for milk production (32)(33)(34). Breast cancer cells also interact with the skeleton resulting in two very common complications, osteolytic bone metastases and hypercalcemia (27,28,76).…”

“…For each experimental sample, a control without reverse transcriptase was run to verify that the amplification product arose from cDNA and not from genomic DNA. The relative expression levels, normalized to glyceraldehyde-3-phosphate dehydrogenase, were determined using the comparative C T method (also known as the 2 ⌬⌬CT method) (32,37). PTHrP mRNA levels were expressed as the fold stimulation or suppression relative to basal expression in unstimulated cells.…”

“…Subsequently, the CaR was shown to be expressed by mammary epithelial cells during lactation in mice (11). However, unlike breast cancer cells, normal mammary epithelial cells suppress PTHrP gene expression and secretion in response to activation of the CaR (11,32). In fact, 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).…”

PTHLH (parathyroid hormone-like hormone)

“…Mammary gland development depends upon a complex interaction between epithelial and mesenchymal cells that requires PTHLH. The calcium sensor (CaR) regulates PTHLH production as well as transport of calcium in the lactating mammary gland (Ardeshirpour et al, 2006). In normal animals, mammary epithelial cells secrete a lot of PTHLH, which helps to adjust maternal metabolism to meet the calcium demands of lactation.…”