FUNCTION OF THE CALCIUM SENSING RECEPTOR IN THE BREAST

描述（由申请人提供）：细胞外钙感应受体（CaR）结合并信号响应Ca++离子。通过协调甲状旁腺激素（PTH）分泌和肾钙处理以响应细胞外钙++的波动，CaR对维持全身钙稳态至关重要。这种受体在乳腺组织和乳腺癌中也有表达。我们发现，在正常小鼠乳腺中，CaR在哺乳期高表达，而在妊娠期不表达。在体外和体内，激活CaR可通过泌乳乳腺上皮细胞（MECs）抑制甲状旁腺激素相关蛋白（PTHrP）的产生。此外，我们已经证明，CaR信号可以促进钙和水的经上皮转运到牛奶中。基于这些数据，我们提出了一个新的范式：乳腺在哺乳期间成为钙感知器官，并积极参与全身钙和骨稳态的调节。我们认为，当钙输送到乳腺下降时，CaR增加PTHrP分泌，以增加母体骨吸收，防止母体低钙血症，恢复产奶所需的钙供应。我们还提出，乳腺CaR匹配钙的运输到乳汁与母体的钙供应。如果钙的供应受到限制，这将通过减少对钙的需求来防止母亲严重的低血钙症。最后，考虑到妊娠期MEC增殖激烈，CaR表达缺失，我们假设CaR信号抑制MEC增殖并促进MEC分化。为了检验这些假设，我们提出了4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检测乳腺PTHrP的产生、水和钙的运输以及母体骨和矿物质的代谢。目的2将研究mec中CaR信号传导对质膜ca++ /ATPase 2 （PMCA2）的调节。目的3将研究介导乳腺CaR对PTHrP产生的调节的信号通路。目的4将通过在转基因小鼠怀孕期间在乳腺中表达一种活化的CaR突变体来研究CaR信号传导对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，并将有助于理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.