Abstract 133: The role of the calcium-sensing receptor (CaSR) in the adaptation of breast cancer cells in high Ca2+ microenvironments

Abstract

Abstract Cancer-induced hypercalcemia (CIH) is common in cancer patients with metastatic disease and in up to 30% of cases without metastasis. During malignancy, tumor cells secrete factors such as parathyroid hormone related protein (PTHrP) that causes the destruction of bone tissue, or osteolysis. The resulting persistent osteolysis leads to a progressive increase in systemic calcium or CIH. High circulating Ca2+ is sensed by the calcium-sensing receptor (CaSR), which plays a significant role in maintaining Ca2+ homeostasis, and also stimulates the secretion of PTHrP which promotes tumor cell proliferation and motility. Moreover, more than 200 mutations including single nucleotide polymorphisms (SNPs) in the CaSR gene have been described, including the inactivating A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 SNPs with reduced sensitivity to Ca2+ . Although the CaSR is the major cell surface Ca2+ sensor in most cell types, its function in the Ca2+ rich bone microenvironment remains unclear. We show that high Ca2+ adaptation of MDA-MB-231 cells, did not lead to altered expression of the receptor in the surviving cells. However, the receptor was desensitized to high Ca2+ and the cells were more motile and formed larger colonies in 3D cultures. Meanwhile, gene expression profiling of triple negative breast cancer cells (TNBC) cells transiently exposed to high Ca2+ reveals the expression of early response genes and Ca2+ -inducible genes with known functions in tumor growth and/or motility. Since breast cancer (BC) frequently metastasizes to skeletal tissues, these data suggest that BC cells that successfully colonize the bone microenvironment undergo high Ca2+ adaptation or priming via the expression of high Ca2+ inducible genes that facilitate cell growth and/or motility. Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Sarrah E. Widatalla, Diva S. Whalen, Stephen D. Williams, Olga Y. Korolkova, Amos M. Sakwe. The role of the calcium-sensing receptor (CaSR) in the adaptation of breast cancer cells in high Ca2+ microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 133.