Tamoxifen has a proliferative effect in endometrial carcinoma mediated via the GPER/EGFR/ERK/cyclin D1 pathway: A retrospective study and an  in vitro  study

Zhang, Lizhi; Li, Yanmin; Lan, Lan; Liu, Rong; Wu, Yanhong; Qu, Quanxin; Wen, Ke

doi:10.1016/j.mce.2016.08.011

Cited by 30 publications

(23 citation statements)

References 37 publications

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“…In addition, it is expressed in the luminal and basal surface of the EC epithelium. Furthermore, GPER was expressed higher in patients receiving tamoxifen treatments (33)(34)(35)(36). Contrarily, a loss in GPER expression in EC tumors compared to the normal endometrium was observed (37), and this was correlated with a high FIGO stage, high histological grade, non-endometrioid histology, aneuploidy, low ERα expression, and disease progression (38).…”

Section: Endometrial Cancermentioning

confidence: 96%

“…On the other hand, in cell lines derived from endometrial tumors, the expression of GPER is also varied, in RL95-2 it is high, in HEC-1A moderate, and in HEC-1B absent (37). Regarding its location, GPER was found at the cytoplasm and plasma membrane of the KLE and RL95-2 cell lines, and in normal endometrium, the location was predominantly intracellular (33,35).…”

Section: Endometrial Cancermentioning

confidence: 96%

“…It has also been described that E2, G-1, OHT, IGF-1, and insulin favor the increased expression of GPER at mRNA and protein levels (35,(40)(41)(42). Several studies have reported that direct stimulation with E2, G-1, and OHT increases the carcinogenic characteristics of EC cell lines, such as proliferation, migration, and invasion, involving mechanisms such as activation of signaling pathways like MAPK and PI3K, calcium influx via Cav1.3 and DAKα, phosphorylation of FAK, and increased production of MMP-2/9, c-Fos, and cyclin D1 (33,35,40,41,(43)(44)(45)(46)(47)(48)(49)(50). However, only one report showed the inhibition of proliferation in RL95-2 and HEC-1A cell lines stimulated with G-1 in a dose-dependent manner (37).…”

Section: Endometrial Cancermentioning

confidence: 97%

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

2020

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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.

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Section: Endometrial Cancermentioning

confidence: 96%

Section: Endometrial Cancermentioning

confidence: 96%

Section: Endometrial Cancermentioning

confidence: 97%

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

2020

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“…However, tumours identified at later stages are associated with high levels of morbidity and mortality with 87% recurrence and distal metastases occurring within three years of primary treatment [ 4 ]. Based on epidemiological studies, oestrogen signalling has been identified as a critical promoter of endometrial carcinogenesis [ 5 ]. It has been observed that oestrogenic signalling is able to contribute to the progression of breast cancer (BC) independent of oestrogen (E2) [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been observed that oestrogenic signalling is able to contribute to the progression of breast cancer (BC) independent of oestrogen (E2) [ 6 ]. Studies have identified various agonists that can initiate the oestrogenic signalling pathway including plant-based phytoestrogens, chemicals such as bisphenol-A (BPA) and therapeutic agents such as selective oestrogen receptor modulators (SERMs) [ 5 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER+ endometrial carcinoma cells

et al. 2017

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Tamoxifen (TAM) is widely used as an adjuvant therapy for women with breast cancer (BC). However, TAM possesses partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial carcinoma (EC). The molecular mechanism for these observations is not well understood. Herein, we demonstrated that forced expression of Trefoil factor 3 (TFF3), in oestrogen receptor-positive (ER+) EC cells significantly increased cell cycle progression, cell survival, anchorage-independent growth, invasiveness and tumour growth in xenograft models. Clinically, elevated TFF3 protein expression was observed in EC compared with normal endometrial tissue, and its increased expression in EC was significantly associated with myometrial invasion. TAM exposure increased expression of TFF3 in ER+ EC cells and its elevated expression resulted in increased oncogenicity and invasiveness. TAM-stimulated expression of TFF3 in EC cells was associated with hypomethylation of the TFF3 promoter sequence and c-JUN/SP1-dependent transcriptional activation. In addition, small interfering (si) RNA-mediated depletion or polyclonal antibody inhibition of TFF3 significantly abrogated oncogenicity and invasiveness in EC cells consequent to TAM induction or forced expression of TFF3. Hence, TAM-stimulated upregulation of TFF3 in EC cells was critical in promoting EC progression associated with TAM treatment. Importantly, inhibition of TFF3 function might be an attractive molecular modality to abrogate the stimulatory effects of TAM on endometrial tissue and to limit the progression of EC.

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Identification of Breast Cancer Inhibitors Specific for G Protein‐Coupled Estrogen Receptor (GPER)‐Expressing Cells

et al. 2017

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To gether with estrogen receptors ERa and ERb,t he Gproteincoupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens andi s currently regardeda sapromising target for ER-negative (ERÀ) and triple-negative( TN) breast cancer.O nly af ew selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtuals creening and cell-based studies for the identification of new chemical scaffoldsw ith as pecific antiproliferative effect against GPER-expressing breast cancer cell lines. Out of the four different scaffolds identified, 8-chloro-4-(4-chlorophenyl)pyrrolo[1,2-a]quinoxaline 14 c was found to be the most promising compound able to induce:1 )antiproliferativea ctivity in GPER-expressing cell lines (MCF7 and SKBR3), similarly to G15;2 )noe ffect on cells that do not expressG PER (HEK293);3 )a decrease in cyclin D1 expression;a nd 4) as ustained induction of cell-cycle negative regulators p53 and p21.Breast cancer is the most common cancer diagnosis in women and the mostc ommon cause of cancer-related mortality among females worldwide, with current predictions and statistics suggesting that both incidence and mortality rates are on the rise. [1] Hormone receptor (HR) positive breast cancer( HR +) is the most common form of breast cancer( 85 %o fa ll breast cancers)a nd has ag ood prognosis thanks to endocrine therapy (e.g.,t amoxifen) and administration of aromatase inhibitors (e.g.,l etrozole). HRÀ human epidermal growth factor receptor 2p ositive (HER2 +), andt riple-negative (TN) breastc ancers (HER2À,E R aÀ,E R bÀ)h ave al ower incidence, but whereas HER2 + tumors can be treated with targeted therapies (e.g., trastuzumab),T Nt umorsh ave the worst prognosis, ag reater chance of recurrence, andnot argeted treatments. [2] Estrogen hormones playakey role not only in the regulation of multiple physiological processes, but also in promoting the proliferation of the neoplastic breast epithelium by acting on soluble nuclear estrogen receptors (ERa and ERb). [3] While tamoxifeni sawidely used selectivee strogen receptorm odulator (SERM) and displays anti-estrogenic (and therefore anticancer) effects in the breast, it also has pro-estrogenic activity in the endometrium, enhancing the risk of developing endometrial cancer. However,t he therapeutic benefito ft amoxifen in the treatment of breast cancer has been considered to outweigh the risk of developinge ndometrial canceri np remenopausal women. [4] These side effects seem to be due to the active metabolite of tamoxifen (4-hydroxytamoxifen, 4-OHT), which acts as an agonistf or at hird estrogenr eceptor involved in the rapid non-genomic response to estrogens:t he Gprotein-coupled estrogen receptor (GPER or GPR30). [5] GPER is now emerging as an ew potentialt arget for the treatment of severalh uman diseases such as cardiovascular,r enal, and proteinuria diseases and malignancy. [6] In the field of anticancer drug disco...

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Tamoxifen has a proliferative effect in endometrial carcinoma mediated via the GPER/EGFR/ERK/cyclin D1 pathway: A retrospective study and an in vitro study

Cited by 30 publications

References 37 publications

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

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

Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER+ endometrial carcinoma cells

Identification of Breast Cancer Inhibitors Specific for G Protein‐Coupled Estrogen Receptor (GPER)‐Expressing Cells

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