The Sigma-1 Receptor – An Investigation of its Potential as a Prognostic Marker and Cancer Selective Target in Breast Cancer

Breast cancer (BCa) remains the leading cause of cancer-related deaths in women worldwide. While the outlook for BCa patients has improved greatly over the past few years, several challenges remain. Up to 40% of hormone receptor positive (HR+) BCa patients, who represent more than 70% of all BCa cases, experience a recurrence after undergoing adjuvant endocrine therapy. Moreover, patients with triple-negative BCa (TNBC), which accounts for nearly 20% of all cases, have no targeted prognostic or therapeutic options and this group experiences higher recurrence rates and poorer survival outcomes compared to other BCa subtypes. The Sigma-1 receptor (Sig1R) has been proposed as a therapeutic target for cancers including BCa. Its functional profile in non-cancerous cells suggests a role in resolving endoplasmic reticulum (EnR) stress and activating the cytoprotective unfolded protein response (UPR). In this thesis, the relevance of Sig1R expression and mechanisms of action of a Sig1R antagonist, 1-(4-iodophenyl)-3-(2-adamantyl)guanidine (IPAG), have been investigated. The Sig1R gene (SIGMAR1) was elevated in BCa, particularly in oestrogen receptor (ER)-negative, Her2-negative (ER-Her2-) patient populations. Its overexpression correlated with shorter recurrence-free and disease-specific survival. This association was also observed at the protein level. Sig1R was differentially expressed across a panel of nine BCa cell lines, and the TNBC cell line MDA-MB-468 had higher protein level expression compared to non-cancerous primary mammary cells (HMECs). Treatment with IPAG induced time and concentration dependent loss of viability in two TNBC cell lines as well as in a Sig1R-low expression, HR+ cell line. HMECs showed negligible loss in viability following exposure to IPAG at a single tested concentration. Upstream of cell death, IPAG caused temporal activation of the three arms of the UPR and induced terminal EnR stress in three examined BCa cell lines. In tamoxifen-resistant LY2 cells, IPAG caused Sig1R to aggregate and co-localize with the stress marker binding immunoglobulin protein (BiP).

These findings show the potential of Sig1R as a novel biomarker for predicting recurrence and survival in BCa patients. The results further demonstrate that treatment with a putative Sig1R antagonist, regardless of levels of Sig1R expression, interferes with the stress-coping mechanisms of BCa cells and thus exposes a novel and exploitable role, particularly for therapeutically refractory subtypes.