The Calcium-Sensing Receptor (CaSR) Variants at rs1801725 Increase the Risk of Developing Secondary Malignant Cancers

The dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. The associated comorbidity is known as cancer-induced hypercalcemia (CIH) which affects up to 30% of cases, in the absence of metastasis. In the course of breast cancer progression, the secretion of parathyroid hormone-related protein (PTHrP) by tumor cells and the associated destruction of bone tissues, leads to a progressive increase in systemic calcium or CIH. The increase in circulating Ca(2+) is sensed by the calcium-sensing receptor (CaSR), which plays a significant role in maintaining Ca(2+) homeostasis. More than 200 mutations and single nucleotide polymorphisms (SNPs) in the CaSR gene have been described, including the A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 SNPs with reduced sensitivity to Ca(2+). Interestingly, high circulating Ca(2+) is associated with aggressive breast tumors in premenopausal women and larger tumors in postmenopausal women; however, the contribution of the CaSR in breast cancer progression remains poorly understood. Unlike SNPs at rs1801726, up to 20% of breast cancer patients with SNPs at rs1801725 may be predisposed to higher circulating Ca(2+) in the course of their disease. Since breast cancer frequently metastasizes to Ca(2+) rich skeletal tissues, we hypothesize that the development of CIH and subsequent desensitization of the CaSR by sustained high Ca(2+) is critical for both the adaptation of TNBC cells to CIH in Ca(2+) rich microenvironments and TNBC progression. Our preliminary data reveal that the expression level and mutational status of the CaSR is cell type-specific, and that sustained high Ca(2+) desensitizes the receptor, but promotes tumor cell growth and motility. Sustained high Ca(2+) also triggers the expression of metastasis promoting genes, including the cancer/testis antigen, MAGEC2, and Plasminogen Activator Inhibitor, PAI-2, potentially via the early response genes FOS/FOSB. In addition, our preliminary data show that the A986S SNP is associated with hypercalcemia, secondary malignancy of bone and respiratory organs, and deficiency of humoral immunity. This study provides novel insights into not only the adaptation of TNBC cells to high circulating Ca(2+), but also suggests that mutations of the CaSR at rs1801725 are predictive of the likelihood for metastasis to lungs and bone.