Breast cancer is one of the most common cancers in women, and the majority of cases have a hormone receptor positive subtype. Though this subtype has several options for treatment, the first-line therapies rely on sensitivity to alterations of estrogen signaling. Estrogen therapy resistance is common and will frequently develop over the treatment course, requiring progression of treatment intensity. Here, work surrounding the sigma-2 receptor pointing towards its involvement in endocrine therapy resistance is summarized, including the involvement of PI3K-mTOR signaling pathway and cholesterol metabolism. Though the identification of the sigma-2 receptor occurred decades ago, its gene was identified more recently, which has allowed for further exploration of its role in tumorigenesis and responses to treatments including endocrine therapy. Given its role in cholesterol homeostasis, particular interest regarding the sigma-2 receptor and estrogen-independent activation of the steroid receptor, estrogen receptor alpha, has been explored.

Breast cancer remains one of the most common cancers in women, in which the majority of cases exhibit a hormone receptor-positive subtype. Although several treatment options are available for patients with this subtype, first-line therapies mainly rely on the patient’s sensitivity to endocrine therapy. Therapy resistance, which frequently develops over the treatment course, remains a key obstacle for clinical intervention. Efforts are currently underway to elucidate additional therapeutic targets to restore endocrine therapy sensitivity and treat hormone receptor-positive breast cancer. Here, we summarize work surrounding the sigma-2 receptor (σ2R) and its potential role in endocrine therapy resistance pathways, including PI3K-mTOR signaling and cholesterol metabolism. Although σ2R was pharmacologically characterized decades ago, its molecular identity remained elusive until 2017, when transmembrane protein 97 (TMEM97) was established as the sigma-2 receptor. TMEM97/σ2R is highly expressed in hormone receptor-positive breast cancer and its RNA expression levels are associated with endocrine resistance. High expression of TMEM97/σ2R elevates estrogen receptor activities and confers breast cancer cells with increased resistance to endocrine therapy via enhanced mTOR signaling. Given the role of TMEM97 in cholesterol homeostasis, understanding the connections between TMEM97/σ2R, breast cancer, and cholesterol regulation may reveal new pathways to aid in the development of targeted therapies. Evidence remains preclinical, and further investigation is needed to confirm hypothesized pathways involving TMEM97/σ2R in breast cancer endocrine resistance.