Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Cancer Gene Therapy volume 30, pages 368–374 (2023)Cite this article

Subjects

A Correction to this article was published on 21 December 2022

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: SIGMAR1 is highly expressed in BCa, particularly in TNBC tumours.
Fig. 2: High gene and protein Sig1R expression correlates with poor clinical outcomes particularly in the ER-Her2- subtype.
Fig. 3: Treatment with IPAG caused Sig1R aggregation, activation of the UPR upstream of cell death.

Similar content being viewed by others

Data availability

The datasets analysed in this study are available at publicly accessible online repositories.

Change history

References

  1. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:1674.

    Article  CAS  Google Scholar 

  2. Park YH, Lee SJ, Cho EY, Choi Y, Lee JE, Nam SJ, et al. Clinical relevance of TNM staging system according to breast cancer subtypes. Ann Oncol. 2011;22:1554–60.

    Article  CAS  Google Scholar 

  3. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12:207.

    Article  Google Scholar 

  4. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Prim. 2019;5:66.

    Article  Google Scholar 

  5. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype. Cancer 2007;109:1721–8.

    Article  Google Scholar 

  6. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.

    Article  Google Scholar 

  7. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750–67.

    Article  CAS  Google Scholar 

  8. Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012;379:432–44.

    Article  CAS  Google Scholar 

  9. Weigelt B, Baehner FL, Reis-Filho JS. The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade. J Pathol. 2010;220:263–80.

    Article  CAS  Google Scholar 

  10. Minckwitz GV, Mueller B, Blohmer JU, Kaufmann M, Eidtmann H, Eiermann W, et al. Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on PCR and survival: results of the GeparTrio trial. J Clin Oncol. 2012;30:1023.

    Article  Google Scholar 

  11. Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 2007;131:596–610.

    Article  CAS  Google Scholar 

  12. Mori T, Hayashi T, Hayashi E, Su TP. Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLoS ONE. 2013;8:e76941.

    Article  CAS  Google Scholar 

  13. Su TP, Su TC, Nakamura Y, Tsai SY. The Sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol Sci. 2016;37:262–78.

    Article  CAS  Google Scholar 

  14. Hetz CA, Soto C. Stressing out the EIR: a role of the unfolded protein response in prion-related disorders. Curr Mol Med. 2006;6:37–43.

    Article  CAS  Google Scholar 

  15. Hetz C, Axten JM, Patterson JB. Pharmacological targeting of the unfolded protein response for disease intervention. Nat Chem Biol. 2019;15:764–75.

    Article  CAS  Google Scholar 

  16. Clarke R, Shajahan AN, Wang Y, Tyson JJ, Riggins RB, Weiner LM, et al. Endoplasmic reticulum stress, the unfolded protein response, and gene network modeling in antiestrogen resistant breast cancer. Horm Mol Biol Clin Investig. 2011;5:35–44.

    CAS  Google Scholar 

  17. Clarke R, Cook KL, Hu R, Facey CO, Tavassoly I, Schwartz JL, et al. Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. Cancer Res. 2012;72:1321–31.

    Article  CAS  Google Scholar 

  18. Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M, et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature 2014;508:103–7.

    Article  CAS  Google Scholar 

  19. Hu R, Warri A, Jin L, Zwart A, Riggins RB, Fang HB, et al. NF-κB signaling is required for XBP1 (unspliced and spliced)-mediated effects on antiestrogen responsiveness and cell fate decisions in breast cancer. Mol Cell Biol. 2015;35:379–90.

    Article  Google Scholar 

  20. Davies MP, Barraclough DL, Stewart C, Joyce KA, Eccles RM, Barraclough R, et al. Expression and splicing of the unfolded protein response gene XBP-1 are significantly associated with clinical outcome of endocrine-treated breast cancer. Int J Cancer. 2008;123:85–8.

    Article  CAS  Google Scholar 

  21. Spruce BA, Campbell LA, McTavish N, Cooper MA, Appleyard MVL, O’Neill M, et al. Small molecule antagonists of the sigma-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo. Cancer Res. 2004;64:4875–86.

    Article  CAS  Google Scholar 

  22. Oyer HM, Sanders CM, Kim FJ. Small-molecule modulators of sigma1 and sigma2/TMEM97 in the context of cancer: foundational concepts and emerging themes. Front Pharmacol. 2019;10:1141.

  23. Xu Q-X, Li E-M, Zhang Y-F, Liao L-D, Xu X-E, Wu Z-Y, et al. Overexpression of Sigma1 receptor and its positive associations with pathologic TNM classification in esophageal squamous cell carcinoma. J Histochem Cytochem. 2012;60:457–66.

    Article  CAS  Google Scholar 

  24. Gueguinou M, Crottès D, Chantôme A, Rapetti-Mauss R, Potier-Cartereau M, Clarysse L, et al. The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca(2+) homeostasis. Oncogene 2017;36:3640–7.

    Article  CAS  Google Scholar 

  25. Schrock JM, Spino CM, Longen CG, Stabler SM, Marino JC, Pasternak GW, et al. Sequential cytoprotective responses to sigma1 ligand–induced endoplasmic reticulum stress. Mol Pharmacol. 2013;84:751–62.

    Article  CAS  Google Scholar 

  26. Thomas JD, Longen CG, Oyer HM, Chen N, Maher CM, Salvino JM, et al. Sigma1 targeting to suppress aberrant androgen receptor signaling in prostate cancer. Cancer Res. 2017;77:2439–52.

    Article  CAS  Google Scholar 

  27. Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, et al. Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol. 2006;24:4236–44.

    Article  CAS  Google Scholar 

  28. Charmsaz S, Hughes É, Bane FT, Tibbitts P, McIlroy M, Byrne C, et al. S100β as a serum marker in endocrine resistant breast cancer. BMC Med. 2017;15:79.

    Article  Google Scholar 

  29. Bronzert DA, Greene GL, Lippman ME. Selection and characterization of a breast cancer cell line resistant to the antiestrogen LY 117018. Endocrinology 1985;117:1409–17.

    Article  CAS  Google Scholar 

  30. Manders EMM, Verbeek FJ, Aten JA. Measurement of co-localization of objects in dual-colour confocal images. J Microsc. 1993;169:375–82.

    Article  CAS  Google Scholar 

  31. Wang B, Rouzier R, Albarracin CT, Sahin A, Wagner P, Yang Y, et al. Expression of sigma 1 receptor in human breast cancer. Breast Cancer Res Treat. 2004;87:205–14.

    Article  CAS  Google Scholar 

  32. Govindan S, Siraganahalli Eswaraiah M, Basavaraj C, Adinarayan M, Sankaran S, Bakre M. Androgen Receptor mRNA levels determine the prognosis in triple-negative breast cancer patients. BMC Cancer. 2020;20:745.

    Article  CAS  Google Scholar 

  33. Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell 2018;173:400–16. e11

    Article  CAS  Google Scholar 

  34. Simony-Lafontaine J, Esslimani M, Bribes E, Gourgou S, Lequeux N, Lavail R, et al. Immunocytochemical assessment of sigma-1 receptor and human sterol isomerase in breast cancer and their relationship with a series of prognostic factors. Br J Cancer. 2000;82:1958–66.

    CAS  Google Scholar 

  35. Jbilo O, Vidal H, Paul R, De Nys N, Bensaid M, Silve S, et al. Purification and characterization of the human SR 31747A-binding protein. A nuclear membrane protein related to yeast sterol isomerase. J Biol Chem. 1997;272:27107–15.

    Article  CAS  Google Scholar 

  36. Lee E, Nichols P, Groshen S, Spicer D, Lee AS. GRP78 as potential predictor for breast cancer response to adjuvant taxane therapy. Int J Cancer. 2011;128:726–31.

    Article  CAS  Google Scholar 

  37. Lee E, Nichols P, Spicer D, Groshen S, Yu MC, Lee AS. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res. 2006;66:7849–53.

    Article  CAS  Google Scholar 

  38. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869.

    Article  Google Scholar 

  39. Dreser A, Vollrath JT, Sechi A, Johann S, Roos A, Yamoah A, et al. The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins. Cell Death Differ. 2017;24:1655–71.

    Article  CAS  Google Scholar 

  40. La X, Zhang L, Li H, Li Z, Song G, Yang P, et al. Ajuba receptor mediates the internalization of tumor-secreted GRP78 into macrophages through different endocytosis pathways. Oncotarget 2018;9:15464–79.

    Article  Google Scholar 

  41. Li R, Yanjiao G, Wubin H, Yue W, Jianhua H, Huachuan Z, et al. Secreted GRP78 activates EGFR-SRC-STAT3 signaling and confers the resistance to sorafeinib in HCC cells. Oncotarget 2017;8:19354–64.

    Article  Google Scholar 

  42. Crouzier L, Denus M, Richard EM, Tavernier A, Diez C, Cubedo N, et al. Sigma-1 receptor is critical for mitochondrial activity and unfolded protein response in larval zebrafish. Int J Mol Sci. 2021;22:11049.

    Article  CAS  Google Scholar 

  43. Oflaz FE, Koshenov Z, Hirtl M, Rost R, Malli R, Graier WF. Sigma-1 receptor modulation by ligands coordinates cancer cell energy metabolism. Biomolecules. 2022;12:762.

    Article  Google Scholar 

  44. Farhadi P, Yarani R, Valipour E, Kiani S, Hoseinkhani Z, Mansouri K. Cell line-directed breast cancer research based on glucose metabolism status. Biomed Pharmacother. 2022;146:112526.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. RCSI Bahrain, Adliya, Bahrain

    Preeti Borde & Stephen T. Safrany

  2. Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland

    Preeti Borde, Nicola Cosgrove, Sara Charmsaz & Leonie Young

Authors
  1. Preeti Borde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicola Cosgrove
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara Charmsaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen T. Safrany
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leonie Young
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Stephen T. Safrany.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-022-00552-4

This article is cited by

Search

Advanced search

Quick links