An investigation of Sigma-1 receptor expression and ligand-induced endoplasmic reticulum stress in breast cancer

• Published in: Cancer gene therapy 2023-02, Vol.30 (2), p.368-374
• Main Authors: Borde, Preeti, Cosgrove, Nicola, Charmsaz, Sara, Safrany, Stephen T., Young, Leonie
• Format: Article
• Language: English
• Subjects: 13/51; 38/39; 631/67/1347; 692/53; 82/29; 96/63; Anthracycline; Biomarkers; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Chemotherapy; Endoplasmic reticulum; Endoplasmic Reticulum Stress; ErbB-2 protein; Female; Gene Expression; Gene Therapy; Guanidine; Humans; Ligands; Protein folding; Receptors, sigma - genetics; Receptors, sigma - therapeutic use; Sigma-1 Receptor; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-022-00552-4

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.