Robinson Taylor S, Osman Mahasin A
Department of Medicine, Division of Oncology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.
Cancers (Basel). 2023 Jul 2;15(13):3464. doi: 10.3390/cancers15133464.
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.
尽管在乳腺癌治疗方面取得了重大进展，但复发仍然是一个问题，三阴性乳腺癌等类型仍然缺乏靶向药物。孤儿西格玛受体1（SigmaR1）已成为乳腺癌的一个靶点，但其作用机制尚不清楚，这阻碍了其临床应用。SigmaR1在器官组织中广泛表达，并定位于各种亚细胞区室，特别是内质网（ER）、线粒体相关膜（MAM）和核膜。因此，它涉及多种细胞功能，包括蛋白质质量控制/内质网应激、钙信号传导、胆固醇稳态、线粒体完整性和能量代谢。因此，SigmaR1与多种癌症和退行性疾病有关，因此作为治疗靶点受到了广泛关注。由于SigmaR1与许多结构不相关的配体结合，它是一个极好的依赖于上下文的治疗靶点。在这里，我们综述了它在乳腺癌中的作用以及基于其已知功能而被考虑的当前治疗方法。由于SigmaR1未被归类为癌蛋白，我们提出了一个模型，其中它在关键细胞途径中作为寡聚化衔接子，这可能有助于阐明其与多种疾病的关联，并为个性化医学的临床应用铺平道路。
