GPER Function in Breast Cancer: An Overview

Abstract

The G-protein-coupled estrogen receptor-1 (GPER, formerly known as GPR30) has attracted increasing interest, considering its ability to mediate estrogenic signaling in different cell types, including the hormone-sensitive tumors like breast cancer. As observed for other GPCR-mediated responses, the activation of the epidermal growth factor receptor is a fundamental integration point in the biological action triggered by GPER. A wide number of natural and synthetic compounds, including estrogens and anti-estrogens, elicit stimulatory effects in breast cancer through GPER up-regulation and activation, suggesting that GPER function is associated with breast tumor progression and tamoxifen resistance. GPER has also been proposed as a candidate biomarker in triple-negative breast cancer, opening a novel scenario for a more comprehensive assessment of breast tumor patients.

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…In addition, our and other studies have largely demonstrated the involvement of GPER in the stimulatory effects elicited by estrogens in cancer cells and tumor microenvironment (6,(9)(10)(11). Significantly, several studies performed in different cell and animal models have ascertained the role exerted by GPER in certain pathological conditions characterized by oxygen deficiency (30,31,(74)(75)(76)(77)(78).…”

“…Consequently, the pharmacological manipulation of certain GPCR-mediated signaling may represent a promising anti-cancer strategy (3,4). As demonstrated for many GPCRs (3,4), the G protein estrogen receptor (GPER, also known as GPR30) may trigger oncogenic signaling (5,6). GPER binds to estrogens, phyto-and xenoestrogens, and also estrogen receptor (ER) antagonists that may act as GPER agonists (7)(8)(9)(10)(11)(12).…”

The G-protein coupled estrogen receptor, GPER: The inside and inside-out story

“…GPER provides further potential complexity for molecular subtyping as a means to assign therapy since steroidal and nonsteroidal ER antagonists (tamoxifen, fulvestrant and raloxifene) have been demonstrated to function as GPER agonists [Filardo, 2011;Petrie et al, 2013;Lappano et al, 2014;Prossnitz and Barton, 2014]. Interestingly, large comparative clinical studies indicate that blockade of estrogen biosynthesis by use of aromatase inhibitors (AIs) has benefit over blockade of the nuclear estrogen receptors as a strategy for treating ER-positive breast cancer.…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…However, as described above, estrogens, as well as other steroids, had also been demonstrated to mediate rapid cellular and physiologic responses, inconsistent with the time frame of transcriptional mechanisms (Falkenstein et al, 2000). The discovery and characterization of a third estrogen receptor in the 2000s (Filardo et al, 2000;Revankar et al, 2005;Thomas et al, 2005), namely GPR30/GPER, belonging to the family of 7-transmembrane G proteincoupled receptors (GPCRs), which classically mediate rapid responses such as kinase activation and ion mobilization, have expanded our understanding of the varied and complex activities of estrogenic compounds throughout the body (Prossnitz, , 2012Prossnitz and Barton, 2009, 2014Prossnitz and Maggiolini, 2009b;Filardo and Thomas, 2012;Han et al, 2013;Srivastava and Evans, 2013;Lappano et al, 2014;Barton and Prossnitz, 2015).…”