Abstract 5432: Cancer-induced hypercalcemia promotes breast cancer progression via AP-1 transcription factor mediated upregulation of malignancy-associated genes

Abstract

Abstract Cancer-induced hypercalcemia (CIH), is common in breast cancer patients with metastatic disease and in up to 30% of cases with solid tumors without evidence of metastasis. However, its role in the development of large and aggressive breast tumors remain poorly understood. In this study, we show that prolong exposure of triple negative breast cancer (TNBC) cells to high Ca2+ is accompanied by reduced sensitivity of the calcium sensing receptor to high Ca2+, increased growth and tumor cell motility. Gene expression profiling of TNBC cells cultured at high Ca2+ (5.0 mM) revealed that in addition to early response genes (FOS/FOSB), high extracellular Ca2+ also modulated the expression of MAGEC2/CT10 and PAI-2 and other malignancy associated genes (MAGs). To determine whether the expression of MAGs is regulated by FOS/FOSB we show that down regulation of FOSB strongly inhibited the high Ca2+-induced expression of MAGEC2 and that FOSB, as a component of the AP-1 transcription factor bound to the MAGEC2 promoter at high Ca2+. We also show that down regulation of MAGEC2 or FOSB affected the migration and proliferation of TNBC cells at high Ca2+. These data suggest that high Ca2+-induced expression of malignancy promoting genes such as MAGEC2/CT10 underlie the successful tumor cell survival, growth and/or motility in calcium-rich microenvironments and presumably, during the hypercalcemia prone late stages of the disease. This research is supported by NIH/NIGMS 5SC2 CA170244 and 1SC1 CA211030, NIH/NCI 2U54CA 163069-07 Citation Format: Heather K. Beasley, Sarrah E. Widatalla, Stephen D. Williams, Diva S. Whalen, Olga Y. Korolkova, Amos M. Sakwe. Cancer-induced hypercalcemia promotes breast cancer progression via AP-1 transcription factor mediated upregulation of malignancy-associated genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5432.