FUNCTION OF THE CALCIUM SENSING RECEPTOR IN THE BREAST

描述（由申请人提供）：细胞外钙敏感受体（CaR）结合并响应Ca++离子发出信号。通过协调甲状旁腺激素（PTH）分泌和肾钙处理响应细胞外Ca++的波动，CaR是维持全身钙稳态的关键。这种受体也在乳腺组织和乳腺癌中表达。我们发现，CaR在哺乳期小鼠乳腺组织中高表达，而在妊娠期不表达。在体外和体内，CaR的激活抑制了哺乳期乳腺上皮细胞（MEC）产生甲状旁腺相关蛋白（PTHrP）。此外，我们已经表明，钙受体信号促进钙和水的跨上皮转运到牛奶。基于这些数据，我们提出了一个新的范例：乳腺在哺乳期成为钙敏感器官，并积极参与全身钙和骨稳态的调节。我们认为，钙受体增加PTHrP分泌时，钙输送到乳腺福尔斯，以增加母体骨吸收，防止母体低钙血症和恢复牛奶生产的钙供应。我们还提出，乳腺钙受体匹配的钙运输到牛奶与母亲的钙供应。如果钙的供应变得有限，这将通过减少需求来保护母亲免受严重的低钙血症。最后，考虑到妊娠期间CaR表达的丧失，即MEC增殖的激烈时期，我们假设CaR信号传导抑制MEC增殖并促进MEC分化。为了验证这些假设，我们提出了四个具体目标。目的1将在乳腺特异性CaR基因缺失的小鼠模型中研究乳腺PTHrP产生、水和钙转运以及母体骨和矿物质代谢。目的2研究CaR信号对MEC质膜Ca++/ATP酶2（PMCA 2）的调节作用。目的3研究乳腺CaR调控PTHrP产生的信号通路。目的4通过在转基因小鼠妊娠期乳腺中表达激活的CaR突变体，研究CaR信号转导对MEC增殖的影响。我们相信，这些研究将加深我们对CaR生理学的理解，并有助于了解乳腺癌患者的骨质疏松症和骨转移。

DESCRIPTION (provided by applicant): The extracellular calcium-sensing receptor (CaR) binds and signals in response to Ca++ ions. By coordinating parathyroid hormone (PTH) secretion and renal calcium handling in response to fluctuations in extracellular Ca++, the CaR is critical to maintaining systemic calcium homeostasis. This receptor is also expressed in breast tissue and in breast cancers. We have found that the CaR is highly expressed in the normal mouse mammary gland during lactation, but is not expressed during pregnancy. Activation of the CaR inhibits the production of parathyroid hormone-related protein (PTHrP) by lactating mammary epithelial cells (MECs) both in vitro and in vivo. Furthermore, we have shown that CaR signaling promotes the transepithelial transport of calcium and water into milk. Based on these data, we propose a new paradigm: that the mammary gland becomes a calcium-sensing organ during lactation and actively participates in the regulation of systemic calcium and bone homeostasis. We propose that the CaR increases PTHrP secretion when calcium delivery to the mammary gland falls in order to increase maternal bone resorption, protect against maternal hypocalcemia and restore the supply of calcium for milk production. We also propose that the mammary CaR matches the transport of calcium into milk with the maternal supply of calcium. This would protect against severe hypocaclemia in the mother by reducing demand if supplies of calcium became limiting. Finally, given the loss of CaR expression during pregnancy, a time of intense MEC proliferation, we hypothesize that CaR signaling inhibits MEC proliferation and promotes MEC differentiation. In order to test these hypotheses we propose 4 Specific Aims. Aim 1 will examine mammary PTHrP production, water and calcium transport and maternal bone and mineral metabolism in a mouse model of mammary-specific CaR gene deletion. Aim 2 will examine the regulation of the plasma membrane Ca++/ATPase 2 (PMCA2) by CaR signaling in MECs. Aim 3 will examine the signaling pathways that mediate the mammary CaR's regulation of PTHrP production. Aim 4 will examine the effects of CaR signaling on MEC proliferation by expressing an activated mutant of the CaR in the mammary gland during pregnancy in transgenic mice. We believe that these studies will deepen our understanding of the physiology of the CaR and will contribute to an understanding of both osteoporosis and bone metastases in patients with breast cancer.