Abstract
Simple SummaryTriple-negative breast cancer (TNBC) lacks all of three treatment targets (estrogen receptor-α, ER-α; progesterone receptor, PgR; and human epidermal growth factor receptor 2, HER2) and is usually associated with a poor clinical outcome; however, several sex steroid receptors, such as androgen receptor (AR), ER-β, and G-protein-coupled estrogen receptor, are frequently expressed and their biological and clinical importance has been suggested. Despite the structural similarity between sex steroid hormones (androgens and estrogens) or receptors (AR and ER-β), similar signaling mechanisms of these hormones, and the coexistence of these hormones and their receptors in TNBC in a clinical setting, most studies or reviews focused on only one of these receptors, and rarely reviewed them in a comprehensive way. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on common and differing features of hormone actions.Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually associated with a poor clinical outcome; however, hormone unresponsiveness, which is the most important biological characteristic of TNBC, only means the lack of nuclear estrogenic signaling through the classical estrogen receptor (ER), ER-α. Several sex steroid receptors other than ER-α: androgen receptor (AR), second ER, ER-β, and non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER), are frequently expressed in TNBC and their biological and clinical importance has been suggested by a large number of studies. Despite the structural similarity between each sex steroid hormone (androgens and estrogens) or each receptor (AR and ER-β), and similarity in the signaling mechanisms of these hormones, most studies or reviews focused on one of these receptors, and rarely reviewed them in a comprehensive way. Considering the coexistence of these hormones and their receptors in TNBC in a clinical setting, a comprehensive viewpoint would be important to correctly understand the association between the carcinogenic mechanism or pathobiology of TNBC and sex steroid hormones. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on the common and divergent features of the action of these hormones.
Highlights
The treatment of breast cancer is primarily involves hormone therapy, anti-human epidermal growth factor receptor 2 (HER2), and chemotherapy [1]
Molecular studies have shown that triple-negative breast cancer (TNBC) can be largely classified into the following categories: (1) Luminal androgen receptor (AR) (LAR), characterized by AR expression; (2) Immunomodulatory (IM), characterized by an active immune response; (3) Basal-like 1 (BL1), characterized by BRCA mutation; (4) Basal-like 2 (BL2), characterized by the expression of myoepithelial markers such as epidermal growth factor receptor (EGFR) or cytokeratin 5/6 (CK5/6); and (5) Mesenchymal/mesenchymal stem-like (M/MSL), characterized by epithelial-mesenchymal transition represented by E-cadherin negativity [10]
We showed that AR-positivity was related to a favorable prognosis in patients aged 75 or over, but not in those aged 55–64, which may at least partly explain the controversial results regarding the prognostic importance of AR in TNBC [111]
Summary
The treatment of breast cancer is primarily involves hormone therapy, anti-human epidermal growth factor receptor 2 (HER2), and chemotherapy [1]. Intra- or peri-tumoral estrogen production is important in ER- and/or PR-positive tumors; TNBC or ER- and PgR-negative tumors, where local estrogen production is less active, are directly affected by the serum hormonal status [42,43]. In such a situation, a comprehensive viewpoint on sex steroid hormones is needed; despite a large number of studies or reviews on TNBC, most of them focused on the action of either androgens or estrogens in TNBC. The pathobiological role of sex steroid hormones in TNBC is reviewed, focusing on the common action and divergent role between androgens and estrogens
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