The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer

Abstract

Estrogens have been implicated in the pathogenesis of various cancers, with increasing concern regarding the overall rising incidence of disease and exposure to environmental estrogens. Estrogens, both endogenous and environmental, manifest their actions through intracellular and plasma membrane receptors, named ERα, ERβ, and GPER. Collectively, they act to promote a broad transcriptional response that is mediated through multiple regulatory enhancers, including estrogen response elements (EREs), serum response elements (SREs), and cyclic AMP response elements (CREs). Yet, the design and rational assignment of antiestrogen therapy for breast cancer has strictly relied upon an endogenous estrogen–ER binary rubric that does not account for environmental estrogens or GPER. New endocrine therapies have focused on the development of drugs that degrade ER via ER complex destabilization or direct enzymatic ubiquitination. However, these new approaches do not broadly treat all cancer-involved receptors, including GPER. The latter is concerning since GPER is directly associated with tumor size, distant metastases, cancer stem cell activity, and endocrine resistance, indicating the importance of targeting this receptor to achieve a more complete therapeutic response. This review focuses on the critical importance and value of GPER-targeted therapeutics as part of a more holistic approach to the treatment of estrogen-driven malignancies.

The G Protein Estrogen Receptor (GPER) is involved in the resistance to the CDK4/6 inhibitor palbociclib in breast cancer

“…2A-B) and T47D/PalbR (Additional File 2C) cells respect to their parental counterparts, in accordance with previous studies [65][66][67]. Considering that the estrogen receptor GPER mediates estrogenic signaling in different cell contexts [10,15,68], we aimed to evaluate whether the expression of GPER may be altered in palbociclib-resistant BC cells. Reminiscing previous RNAsequencing data [69], we found that the expression of GPER is increased at both the mRNA and protein levels in MCF7/PalbR (Fig.…”

“…The ligands are also shown separately: palbociclib (B), G-1 (C) and E2 (D). E ERK1/2 phosphorylation in CAFs transiently transfected with a control shRNA or a shGPER plasmid and then exposed for 15 Additional File 6B-C). Interestingly, palbociclib treatment reduced the viability only in MCF7 and T47D cells co-cultured with CAFs silenced for GPER expression (Fig.…”

“…The transmembrane G protein-coupled estrogen receptor (GPER) has been shown to mediate stimulatory effects elicited by estrogens, estrogen-like compounds and even antiestrogens in normal and malignant cells, including BC cells [8][9][10]. In particular, GPER signaling may trigger transcriptional events toward the stimulation of growth, migration, invasion and pro-inflammatory responses in BC cells [10][11][12][13][14][15]. Of note, GPER has been implicated in both the resistance to the ER antagonist tamoxifen and the up-regulation of aromatase levels, therefore leading to proliferative effects in tamoxifenresistant BC cells [16][17][18].…”

Bisphenol-A in Drinking Water Accelerates Mammary Cancerogenesis and Favors an Immunosuppressive Tumor Microenvironment in BALB–neuT Mice

“…Therefore, even though in BALB– neu T mice, αER expression appears to be lost at an early stage of ErbB2/ neu -driven carcinogenesis, BPA can nonetheless promote tumor progression by acting via GPR30. Indeed, besides the well-known role of αER-mediated genomic and non-genomic pathways in enhancing breast cancer cell proliferation, survival, and invasion [ 65 , 66 ], a key role in estrogen-dependent responses and in the progression of breast cancer is played by GPR30 [ 67 , 68 , 69 , 70 ], and it has been previously demonstrated that GPR30 can mediate BPA estrogenic signals in ER-negative breast cancer cells [ 44 , 71 ]. While it is reported that about 60% of human breast cancers are positive for GPR30 expression [ 68 ], that mammary tumors of BALB– neu T mice express high levels of this alternative ER has not been reported before to our knowledge and highlights that these transgenic mice represent a valuable model to investigate the crosstalk between GPR30 and ErbB2/ neu in vivo [ 72 ].…”

The G Protein-Coupled Estrogen Receptor GPER in the Development and Progression of Cancer

“…GPER has been demonstrated to play a pivotal role in various physiological and pathological processes across the immune, cardiovascular, endocrine, nervous, and reproductive systems [3,4]. Consequently, GPER is now recognized as a novel therapeutic target or prognostic marker in a range of pathologies, including cancer [8][9][10][11][12]. Here, we aim to provide a comprehensive summary of the current understanding of GPER's role in various cancer types.…”