O26: Sigma Receptors in Breast Cancer – examining Their Ligand Mediated Mechanisms of Cancer Cell Death and Potential for Clinical Diagnostics

Abstract

Introduction Sigma receptors (SRs) are regularly overexpressed in cancer however their functions remain unknown. Certain Sigma1-receptor (Sig1R) ligands trigger death in breast cancer (BCa) cells but not in non-cancerous breast cells (NCB). In stressed cells, Sig1R is vital to the pro-survival unfolded protein response (UPR). Cancer cells depend on UPR signalling for survival, investigating Sig1R mediated mechanisms in BCa vs. NCB might uncover novel and targetable weaknesses in cancer. Method UPR activation by Sig1R antagonist IPAG was examined in BCa cells by Western blotting. Sig1R and UPR marker localizations were examined by immunofluorescence. SR gene expression between 141 matched breast tumour tissue and tumour adjacent normal samples was compared using RNAseq data from The Cancer Genome Atlas (TCGA). Merged microarray datasets were used to compare SR expression in 399 primary breast tumours with relapse (BCaR) vs. 352 without relapse (BCaNR). Result Relative to non-cancerous human mammary epithelial cells, Sig1R expression was lowest in MCF7s and highest in MDA-MB-468s. IPAG induced differential temporal activation of all three branches of the UPR in MCF7 and tamoxifen-resistant, low Sig1R expressing cell line LY2. TCGA RNAseq data highlighted SR overexpression in BCa particularly in the basal subtype. Microarray data showed both oestrogen receptor (ER)+ and ER- BCaR primaries had elevated SIGMAR1 compared to BCaNR primaries of the same respective ER status. Conclusion BCa cells are dependent on Sig1R mediated signalling. Sig1R expression might indicate the propensity of breast tumours to relapse. Thus, Sig1R represents a potential target in BCa, particularly for aggressive subtypes. Take-home message The Sigma-1 receptor (Sig1R) has a vital but unknown pro-survival function in cancer; Sig1R ligands cause death in cancer cells while sparing non-cancerous ones. Characterizing Sig1R mediated signalling may reveal novel, selective therapeutic targets in cancer.