TMCO1 is upregulated in breast cancer and regulates the response to pro-apoptotic agents in breast cancer cells

Abstract

The release of Ca2+ ions from endoplasmic reticulum calcium stores is a key event in a variety of cellular processes, including gene transcription, migration and proliferation. This release of Ca2+ often occurs through inositol 1,4,5-triphosphate receptors and the activity of these channels and the levels of stored Ca2+ in the endoplasmic reticulum are important regulators of cell death in cancer cells. A recently identified Ca2+ channel of the endoplasmic reticulum is transmembrane and coiled-coil domains 1 (TMCO1). In this study, we link the overexpression of TMCO1 with prognosis in node-positive basal breast cancer patients. We also identify interacting proteins of TMCO1, which include endoplasmic reticulum-resident proteins involved in Ca2+ regulation and proteins directly involved in nucleocytoplasmic transport. Interacting proteins included nuclear transport proteins and TMCO1 was shown to have both nuclear and endoplasmic reticulum localisation in MDA-MB-231 basal breast cancer cells. These studies also define a role for TMCO1 in the regulation of breast cancer cells in their sensitivity to BCL-2/MCL-1 inhibitors, analogous to the role of inositol 1,4,5-triphosphate receptors in the regulation of cell death pathways activated by these agents.