Abstract 1567: The role of the calcium-sensing receptor (CaSR) in the bone metastatic niche

Cancer-induced hypercalcemia (CIH) is common in cancer patients with metastatic disease and in up to 30% of breast cancer cases without evidence of metastasis. During malignancy, tumor cells-including triple negative breast cancer (TNBC) cells, secrete factors such as parathyroid hormone-related protein (PTHrP) that causes the osteolysis. As cancer progresses, it becomes inevitable that the increase in tumor cell derived PTHrP and the associated persistent osteolysis, leads to a progressive increase in systemic calcium (Ca2+) or CIH. The resulting increase in circulating Ca2+ is sensed by the calcium-sensing receptor (CaSR), which not only plays a significant role in maintaining Ca2+ homeostasis but also promotes tumor cell proliferation and motility. High circulating Ca2+ is associated with aggressive tumors in premenopausal women and larger tumors in postmenopausal women, but the contribution of the CaSR remains poorly understood. Since breast cancer frequently metastasizes to Ca2+-rich skeletal tissues, the goal of this study is to gain a better understanding of the role of CaSR in the adaptation of TNBC cells to high Ca2+ and subsequent survival in Ca2+ rich environments. More than 200 mutations, including single nucleotide polymorphisms (SNPs) in exon 7 of the CaSR gene, have been described. These include the inactivating A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 with reduced sensitivity to Ca2+. Unlike SNPs at rs1801726, up to 20% of breast cancer patients with SNPs at rs1801725 may be predisposed to higher circulating Ca2+ in the course of their disease. Our preliminary data reveal that the expression level and mutational status (in exon 7) of the CaSR is cell type specific, where sustained high Ca2+ desensitizes the receptor, but promotes tumor cell growth and motility. Sustained high Ca2+ triggers growth and the expression of metastasis promoting genes including the cancer/testis (melanoma) antigen, MAGEC2 and Plasminogen Activator Inhibitor, PAI-2, potentially via the early response genes FOS/FOSB. Moreover, our preliminary data showed that the A986S SNP is associated with hypercalcemia and secondary malignancy of bone, while the Q1011E SNP is associated with osteoporosis. We hypothesize that desensitization of the CaSR by sustained high Ca2+ is critical for both the adaptation of TNBC cells to CIH, and their survival in Ca2+ rich microenvironments. To test this hypothesis, we will determine whether high Ca2+ inducible genes/proteins underlie the adaptation of TNBC cells in high Ca2+ microenvironments. We anticipate that data from this proposed study will provide novel insights into the adaptation of TNBC cells in high Ca2+ prior to metastasis. This proposed research will study how the differences in the functional status of the CaSR (A986S in Caucasians and Q1011E in African Americans) may predispose breast cancer patients to rapid progression of advanced forms of breast cancer and becoming hypercalcemic. Citation Format: Heather K. Beasley, Ky9Era Actkins, Annika Faucon, Diva Whalen, Stephen Williams, Olga Korolkova, Amos Sakwe. The role of the calcium-sensing receptor (CaSR) in the bone metastatic niche [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1567.