Abstract
Targeted therapeutic options and prognostic biomarkers for hormone receptor- or Her2 receptor-negative breast cancers are severely limited. The sigma-1 receptor, a stress-activated chaperone, is frequently dysregulated in disease. However, its significance in breast cancer (BCa) has not been adequately explored. Here, we report that the sigma-1 receptor gene (SIGMAR1) is elevated in BCa, particularly in the aggressive triple-negative (TNBC) subtype. By examining several patient datasets, we found that high expression at both the gene (SIGMAR1) and protein (Sig1R) levels associated with poor survival outcomes, specifically in ER-Her2- groups. Our data further show that high SIGMAR1 was predictive of shorter survival times in patients treated with adjuvant chemotherapy (ChT). Interestingly, in a separate cohort who received neoadjuvant taxane + anthracycline treatment, elevated SIGMAR1 associated with higher rates of pathologic complete response (pCR). Treatment with a Sig1R antagonist, 1-(4-iodophenyl)-3-(2-adamantyl)guanidine (IPAG), activated the unfolded protein response (UPR) in TNBC (high-Sig1R expressing) and ER + (low-Sig1R expressing) BCa cell lines. In tamoxifen-resistant LY2 cells, IPAG caused Sig1R to aggregate and co-localise with the stress marker BiP. These findings showcase the potential of Sig1R as a novel biomarker in TNBC as well as highlight its ligand-induced interference with the stress-coping mechanisms of BCa cells.
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Data availability
The datasets analysed in this study are available at publicly accessible online repositories.
Change history
21 December 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41417-022-00579-7
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Acknowledgements
We gratefully acknowledge the contributions of Dr Katherine Sheehan and Joanna Fay at Beaumont Hospital, Dublin for carrying out the IHC staining. We thank Dr Sheehan and Fiona Bane (RCSI Dublin) for helping to score the TMA. This work was funded by the Dilmun Scholar Programme, RCSI-Bahrain.
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PB, STS and LY designed the study. PB performed the in vitro experiments and generated the figures. PB and NC acquired, analysed and interpreted in silico data, PB generated the figures. SC generated the IHC related results and graphs. STS and LY supervised the research. PB wrote the manuscript. PB, NC, STS and LY provided feedback on the manuscript.
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Borde, P., Cosgrove, N., Charmsaz, S. et al. An investigation of Sigma-1 receptor expression and ligand-induced endoplasmic reticulum stress in breast cancer. Cancer Gene Ther 30, 368–374 (2023). https://doi.org/10.1038/s41417-022-00552-4
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DOI: https://doi.org/10.1038/s41417-022-00552-4
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