Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone-Related Protein.

Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo. Tissue-specific disruption of the casr gene in mammary epithelial cells in MMTV-PymT mice reduced tumor PTHrP expression and inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27kip1 levels and prevented nuclear accumulation of the pro-apoptotic factor AIF. Taken together, our findings suggest that CaSR-PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression.

甲状旁腺激素相关蛋白（PTHrP）通过促进高钙血症、肿瘤生长和溶骨性骨转移，促进乳腺癌的发展和转移进程，但目前尚不清楚在乳腺肿瘤中PTHrP是如何上调的。在此，我们通过对乳腺癌MMTV - PymT转基因小鼠模型以及人乳腺癌细胞中CaSR - PTHrP相互作用的研究，报道了钙敏感受体（CaSR）在此过程中的核心作用，CaSR能使细胞对细胞外钙的变化作出反应。在体外和体内，CaSR激活均可刺激乳腺癌细胞产生PTHrP。在MMTV - PymT小鼠中乳腺上皮细胞的casr基因的组织特异性破坏可降低肿瘤中PTHrP的表达，并抑制肿瘤细胞增殖和肿瘤生长。CaSR信号传导促进人乳腺癌细胞系以及从MMTV - PyMT小鼠培养的肿瘤细胞的增殖。此外，CaSR激活可抑制由高细胞外钙浓度引发的细胞死亡。CaSR的作用似乎是由PTHrP的核作用介导的，PTHrP可降低p27kip1水平并阻止促凋亡因子AIF的核积聚。综上所述，我们的研究结果表明，CaSR - PTHrP相互作用可能是开发治疗药物的一个有前景的靶点，用于限制骨转移以及其他钙和/或PTHrP水平升高促进乳腺癌进展的微环境中的肿瘤细胞生长。