Estrogen Actions in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER) α, but the expression of estrogen receptors ERβ and G protein-coupled estrogen receptor 1 (GPER-1) is able to trigger estrogen-responsivity in TNBC. Estrogen signaling in TNBC can also be activated and modulated by the constitutively active estrogen-related receptors (ERRs). In this review article, we discuss the role of ERβ and GPER-1 as mediators of E2 action in TNBC as well as the function of ERRs as activators and modulators of estrogen signaling in this cancer entity. For this purpose, original research articles on estrogen actions in TNBC were considered, which are listed in the PubMed database. Additionally, we performed meta-analyses of publicly accessible integrated gene expression and survival data to elucidate the association of ERβ, GPER-1, and ERR expression levels in TNBC with survival. Finally, options for endocrine therapy strategies for TNBC were discussed.

Keywords: G-protein coupled estrogen receptor 1; estrogen; estrogen receptor; estrogen-related receptor; triple-negative breast cancer.

Figure 1

Comparison of the molecular subclassification systems applied to triple-negative breast cancers (TNBCs) by the PAM50 assay (Prosigna) and by Lehmann et al. [8]. The basal-like (BL) 1, BL2, immune-modulatory (IM) and mesenchymal (M) subclasses are preferentially of the PAM50 basal-like intrinsic subtype. UNC = unspecified.

Figure 2

Schematic overview of estrogen signaling in TNBC cells. cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; CREB: cAMP-response element binding protein; CRE: cAMP-response element; SRE: serum response element; MMP: matrix metalloproteinase; HB-EGF: heparin-binding EGF-like growth factor; EGFR: epidermal growth factor receptor; MEK: Mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B (PKB). Further abbreviations are addressed in the text.

Figure 3

Kaplan–Meier analyses of the impact of ERβ mRNA expression on relapse-free survival (RFS) of patients with TNBC of the indicated 6 subtypes identified by Lehmann et al. [8] using the integrated microarray and clinical data KMplotter platform [56].

Figure 4

Kaplan–Meier analyses of the impact of ERR mRNA expression on relapse-free survival (RFS) of 879 patients with basal-like TNBC using the integrated microarray and clinical data KMplotter platform [56]. Indicated are the genes coding for ERRα, β, and γ.

Figure 5

Kaplan–Meier analyses of the impact of ERRβ mRNA expression on relapse-free survival (RFS) of patients with the indicated TNBC subtypes identified by Lehmann et al. [8] using the integrated microarray and clinical data KMplotter platform [56]. The subtypes not indicated here did not show any association between ERRβ expression and survival.