Abstract 5040: Calcium channels: Potential new therapeutic targets for hormone independent and resistant breast cancers

Abstract

Estrogen receptor alpha (ERα) is central to the growth and progression of a subset of breast cancers. As such, therapies that target ERα are a standard of care in the treatment of ERα -positive disease. Unfortunately, one-third of patients receiving hormonal therapies develop resistance. Several factors are believed to contribute to resistance including increased hormone independent activation of ERα by activated signal transduction pathways such as the epidermal growth factor (EGF) signaling pathway. We have shown that calcium mediates the cross talk between the EGF signaling pathway and ERα by directly binding to and activating the ligand binding domain of ERα suggesting a role for calcium in the development and progression of hormone independent and resistant breast cancer. Preliminary results from this study show that compared to normal (MCF10A) or hormone dependent (MCF-7) breast cells, hormone independent and resistant breast cancer cells (MCF7-2A, LCC-9, and MCF7-RR) have higher expression of the L-type and T-type calcium channels and higher concentrations of intracellular calcium. When hormone resistant (LCC-9) cells were treated with the intracellular calcium chelator BAPTA-AM, the L-type calcium channel blocker methoxyverapamil, or the T-type calcium channel blocker mibefradil, there was a significant decrease in the expression of the ERα regulated gene progesterone receptor that was reversed by the addition of estradiol. More importantly, when hormone independent (MCF7-2A) and hormone independent (LCC-9) cells were treated with the calcium channel blockers, there was in a significant decrease in growth and a re-sensitization of the antiestrogen resistant LCC-9 cells to tamoxifen and fulvestrant. Taken together, the preliminary results suggest that increased expression of calcium channels and intracellular calcium contribute to the hormone independent activation of ERα and point to a potential new therapeutic target for hormone independent and resistant breast cancer. Citation Format: Kedra Cyrus, Mudit Kaushal, Zeina Sharawi, Glyn Noguchi, Tiffany Chang, William Rydzewski, Fatima Gibrel, William Yeguech, Bassam Haddad, Mary Beth Martin. Calcium channels: Potential new therapeutic targets for hormone independent and resistant breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5040. doi:10.1158/1538-7445.AM2015-5040