Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones

Abstract

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.

The Physiological Mechanisms of Triple Negative Breast Cancer in African American Women

“…Androgen activation or expression can be upregulated, leading to tumorigenesis through genomic signaling. 30 The early onset of TNBC that is androgen receptor positive can be associated with higher serum levels of estrogen/androgen in premenopausal women. 30 Estrogen's role, in particular, has significant downstream effects.…”

“…30 The early onset of TNBC that is androgen receptor positive can be associated with higher serum levels of estrogen/androgen in premenopausal women. 30 Estrogen's role, in particular, has significant downstream effects. In oral contraceptive use, it can stimulate angiogenesis, ER binding, and stromal cell recruitment leading to cancer development.…”

Androgen and Estrogen β Receptor Expression Enhances Efficacy of Antihormonal Treatments in Triple-Negative Breast Cancer Cell Lines

“…This classification is based on genetic profiles dividing TNBC into basal-like 1 (BL1), basallike 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem like (MSL) and luminal androgen receptor (LAR) subtypes [13,14]. Although TNBC is characterized by the lack of expression of ERα, PR and HER-2 overexpression, this breast cancer subtype is capable of expressing other receptors like the androgen receptor (AR) or the estrogen receptor β (ERβ) [8,15,16]. The AR is present in around 10-43% of cases of TNBC [8,15,17].…”

“…Thus, the AR has been postulated to be a promising target for future therapies against TNBC [11]. On the other hand, ERβ has been of interest because of its presence in around 30% of TNBC cases [15,16]. The ERβ role in TNBC is controversial among research; however, it has been observed to be clearly involved in TNBC development processes [20].…”

“…They are sex steroids derived from cholesterol and they are mainly secreted from the ovaries and the adrenal cortex [21]. Cholesterol can be converted to dihydroepiandrostenedione (DHEA) and androstenedione (A4), which are the main steroid precursors of androgens and estrogens [16]. The 3β-hydroxysteroid dehydrogenase (3βHSD) enzyme converts DHEA in A4 and the 17β-hydroxysteroid dehydrogenase (17βHSD) converts T from A4 [16].…”