Citation: Robinson, T.S.; Osman, M.A. An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer. Cancers 2023, 15, 3464. https://doi.org/10.3390/ cancers15133464 Academic Editors: Evgeny Yakirevich and Yihong Wang Received: 7 May 2023 Revised: 5 June 2023 Accepted: 7 June 2023 Published: 2 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Review An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer Taylor S. Robinson and Mahasin A. Osman * Department of Medicine, Division of Oncology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; taylor.robinson@rockets.utoledo.edu * Correspondence: mahasin.osman@utoledo.edu or mo28@Cornell.edu Simple Summary: Breast cancer continues to be the number one cause of cancer mortality among women. Because breast cancer is a heterogenous disease there is a need for a more personalized approach to treatment. Such an approach requires the understanding of the molecular root cause of each cancer and the identification of the responsible molecule(s) or pathway(s). SigmaR1 is a receptor implicated in certain types of breast cancer and represents a promising target for a new generation of personalized treatments. However, there is a need for understanding its precise cellular role in order to target it effectively. This article reviews the current knowledge about SigmaR1 in breast cancer biology and potential treatment and proposes a new model as to how SigmaR1 operates within the cell in order to devise new effective ways for utilizing it in the clinic. Abstract: Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub- cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine. Keywords: breast cancer biomarker; sigma receptor1; breast cancer; oligomerization; IQGAP1; Cdc42; Rac1 1. Introduction Breast cancer is a heterogeneous collection of diseases that have been classified into at least four molecular subtypes that require a complex regimen of treatments [1]. Though much progress has been made in curing early-stage breast cancer, the development of resistance, recurrence, and metastatic disease remains the driver of the current rise in disease incidence and mortality [2]. Additionally, the triple-negative breast cancer (TNBC) subtype, itself is heterogenous and lacks targeted therapy [3]. Accordingly, approaches for personalized medicine have been highly sought after [2], including the identification of new molecular targets. Mounting evidence has presented Sigma receptor 1 (SigmaR1) as a potential target in the diagnosis and treatment of breast cancer. Cancers 2023, 15, 3464. https://doi.org/10.3390/cancers15133464 https://www.mdpi.com/journal/cancers