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ORAI1 and ORAI3 in breast cancer molecular subtypes and the identification of ORAI3 as a hypoxia sensitive gene and a regulator of hypoxia responses
Citation
Azimi, I and Milevskiy, MJG and Chalmers, SB and Yapa, KTDS and Robitaille, M and Henry, C and Baillie, GJ and Thompson, EW and Roberts-Thomson, SJ and Monteith, GR, ORAI1 and ORAI3 in breast cancer molecular subtypes and the identification of ORAI3 as a hypoxia sensitive gene and a regulator of hypoxia responses, Cancers, 11, (2) Article 208. ISSN 2072-6694 (2019) [Refereed Article]
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Copyright Statement
Copyright 2019 The Author(s) Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/
DOI: doi:10.3390/cancers11020208
Abstract
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 ORAI1 and ORAI3 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 ORAI1 is a feature of basal-like breast cancers, while elevated ORAI3
is a feature of luminal breast cancers. Intriguingly, we found that ORAI3 is over-expressed in the
mesenchymal subtype of triple-negative breast cancer. Given this, we assessed ORAI3 levels in the
presence 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 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 ORAI3 levels were not associated with survival; basal, estrogen receptor-negative
and triple-negative breast cancers with high ORAI3 and low ORAI1 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.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | cancer, signal transduction, calcium, hypoxia |
| Research Division: | Biological Sciences |
| Research Group: | Biochemistry and cell biology |
| Research Field: | Signal transduction |
| Objective Division: | Health |
| Objective Group: | Clinical health |
| Objective Field: | Clinical health not elsewhere classified |
| UTAS Author: | Azimi, I (Dr Iman Azimi) |
| ID Code: | 131091 |
| Year Published: | 2019 |
| Web of Science® Times Cited: | 33 |
| Deposited By: | Pharmacy |
| Deposited On: | 2019-02-28 |
| Last Modified: | 2022-08-25 |
| Downloads: | 37 View Download Statistics |
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