Expression and Role of the G Protein-Coupled Estrogen Receptor (GPR30/GPER) in the Development and Immune Response in Female Reproductive Cancers

Abstract

Cancer is a major public health issue and represents the second leading cause of death in women worldwide, as female reproductive-related neoplasms are the main cause of incidence and mortality. Female reproductive cancers have a close relationship to estrogens, the principal female sex steroid hormones. Estrogens exert their actions by the nuclear estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). ERα, and ERβ act as transcription factors mediating genomic effects. Besides, the G protein-coupled estrogen receptor (GPER, formerly known as GPR30) was recently described as a seven-transmembrane receptor that mediates non-genomic estrogenic signaling, including calcium mobilization, cAMP synthesis, cleavage of matrix metalloproteinases, transactivation of epidermal growth factor receptor (EGFR), and the subsequent activation of PI3K and MAPK signaling pathways, which are the reasons why it is related to cellular processes, such as cell-cycle progression, cellular proliferation, differentiation, apoptosis, migration, and invasion. Since its discovery, selective agonists and antagonists have been found and developed. GPER has been implicated in a variety of hormone-responsiveness tumors, such as breast, endometrial, ovarian, cervical, prostate, and testicular cancer as well as lung, hepatic, thyroid, colorectal, and adrenocortical cancers. Nevertheless, GPER actions in cancer are still debatable due to the conflicting information that has been reported to date, since many reports indicate that activation of this receptor can modulate carcinogenesis. In contrast, many others show that its activation inhibits tumor activity. Besides, estrogens play an essential role in the regulation of the immune system, but little information exists about the role of GPER activation on its modulation within cancer context. This review focuses on the role that the stimulation of GPER plays in female reproductive neoplasms, specifically breast, endometrial, ovarian, and cervical cancers, in its tumor activity and immune response regulation.

Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones

“…Although TNBC is defined as negative for both ER-α and PgR, some TNBC express other sex steroid hormone receptors: AR [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], ER-β [ 27 , 28 , 29 , 30 , 31 , 32 ], or GPER [ 33 , 34 , 35 , 36 , 37 , 38 ]. AR and ER-β belong to the ER type subgroup of the nuclear receptor superfamily, and typically transmit genomic signaling; however, the existence of non-genomic signaling pathways through these receptors or non-nuclear receptors located in the cytoplasmic membrane or cytoplasm has been reported and attracted attention.…”

“…The presence and importance of non-nuclear-located sex steroid hormone receptors have been suggested from the finding of rapid actions induced by estrogens or androgens on various type of cells or tissues, which occurs within minutes after stimulation [ 33 , 34 , 69 ]. The underlying mechanism behind the rapid action has been intensively studied, and proved to be through specific kinases and modulation of a significant number of cellular processes ( Figure 3 ).…”

“…GPER activated by ligand binding causes various reactions, including pathways such as: (1) cAMP production leading to PKA/CREB activation; (2) mobilization of calcium from the endoplasmic reticulum through activation of phospholipase C (PLC); (3) activation of SRC proteins promoting the activation of MMP-2/9, resulting in EGFR transactivation, leading to the activation of MAPK, ERK1/2, PI3K/Akt/mTOR, and NFκB ( Figure 3 ), etc. [ 33 , 34 ]. The presence of GPCR for androgens (GP“AR”) has long been suggested, and recently, GPRC6A, ZIP9, and OXER1 were proved to have the ability to act as membrane androgen receptors [ 12 , 69 ].…”

“…Hormone (estrogen) unresponsiveness is considered the fundamental characteristic of TNBC; however, studies have revealed the expression of some sex steroid hormone receptors other than classic ER (now renamed ER-α) in TNBC; that is, androgen receptor (AR) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ], second ER (namely ER-β) [ 27 , 28 , 29 , 30 , 31 , 32 ], or non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER) [ 33 , 34 , 35 , 36 , 37 , 38 ]; suggesting the biological and/or clinical relevance of sex steroid hormones in TNBC. Physiologically present androgens and estrogens are made of cholesterol, and commonly have a steroidal structure [ 39 , 40 , 41 ].…”

“…Physiologically present androgens and estrogens are made of cholesterol, and commonly have a steroidal structure [ 39 , 40 , 41 ]. Further, the action of these hormones is exerted through similar mechanisms, not only involving nuclear transcription but also crosstalk with various intracytoplasmic pathways [ 12 , 29 , 33 , 34 ]. Physiologically, androgens and estrogens are present in the body, with various rates among organs or individuals.…”