ORAI1 and ORAI3 in breast cancer molecular subtypes and the identification of ORAI3 as a hypoxia sensitive gene and a regulator of hypoxia responses

The remodeling of specific calcium-permeable ion channels is a feature of some breastcancer subtypes. ORAI1 is a protein that forms a calcium-permeable ion channel responsiblefor 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 manyestrogen receptor-positive breast cancer cell lines, where it also controls proliferation. ORAI1is a well-characterized regulator of the proliferation and migration of many basal breast cancercells; however, the role of ORAI3 in these types of breast cancer cells remains unclear. Here, wesought to define ORAI1 and ORAI3 expression in breast cancer cell lines of different molecularsubtypes and assess the potential role and regulation of ORAI3 in basal breast cancer cells. Our studydemonstrates that elevated ORAI1 is a feature of basal-like breast cancers, while elevated ORAI3is a feature of luminal breast cancers. Intriguingly, we found that ORAI3 is over-expressed in themesenchymal subtype of triple-negative breast cancer. Given this, we assessed ORAI3 levels in thepresence of two inducers of the mesenchymal phenotype, hypoxia and epidermal growth factor(EGF). Hypoxia induced ORAI3 levels in basal breast cancer cell lines through a pathway involvinghypoxia-inducible factor-1 alpha (HIF1α). The silencing of ORAI3 attenuated hypoxia-associatedphosphorylation of the EGF receptor (EGFR) and the expression of genes associated with cellmigration and inflammatory/immune responses in the MDA-MB-468 model of basal breast cancer.Although elevated ORAI3 levels were not associated with survival; basal, estrogen receptor-negativeand triple-negative breast cancers with high ORAI3 and low ORAI1 levels were associated withpoorer clinical outcomes. This study defines ORAI3 as a potential fine-tuner for processes relevant tothe progression of basal breast cancers