| Summary: | The remodeling of specific calcium-permeable ion channels is a feature of some breast cancer subtypes. ORAI1 is a protein that forms a calcium-permeable ion channel responsible for store-operated calcium entry (SOCE) in a variety of cell types. ORAI3, a related isoform, is not a regulator of SOCE in most cell types. However, ORAI3 does control SOCE in many estrogen receptor-positive breast cancer cell lines, where it also controls proliferation. ORAI1 is a well-characterized regulator of the proliferation and migration of many basal breast cancer cells; however, the role of ORAI3 in these types of breast cancer cells remains unclear. Here, we sought to define <i>ORAI1</i> and <i>ORAI3</i> expression in breast cancer cell lines of different molecular subtypes and assess the potential role and regulation of ORAI3 in basal breast cancer cells. Our study demonstrates that elevated <i>ORAI1 </i>is a feature of basal-like breast cancers, while elevated <i>ORAI3</i> is a feature of luminal breast cancers. Intriguingly, we found that <i>ORAI3</i> is over-expressed in the mesenchymal subtype of triple-negative breast cancer. Given this, we assessed <i>ORAI3</i> levels in the presence of two inducers of the mesenchymal phenotype, hypoxia and epidermal growth factor (EGF). Hypoxia induced <i>ORAI3</i> levels in basal breast cancer cell lines through a pathway involving hypoxia-inducible factor-1 alpha (HIF1α. The silencing of ORAI3 attenuated hypoxia-associated phosphorylation of the EGF receptor (EGFR) and the expression of genes associated with cell migration and inflammatory/immune responses in the MDA-MB-468 model of basal breast cancer. Although elevated <i>ORAI3</i> levels were not associated with survival; basal, estrogen receptor-negative and triple-negative breast cancers with high <i>ORAI3</i> and low <i>ORAI</i><i>1</i> levels were associated with poorer clinical outcomes. This study defines ORAI3 as a potential fine-tuner for processes relevant to the progression of basal breast cancers.
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