Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

Bossard, Carine; Busson, Muriel; Vindrieux, David; Gaudin, Françoise; Machelon, Véronique; Brigitte, Madly; Jacquard, Carine; Pillon, Arnaud; Balaguer, Patrick; Balabanian, Karl; Lazennec, Gwendal

doi:10.1371/journal.pone.0044787

Cited by 100 publications

(103 citation statements)

References 55 publications

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“…Although the contradictory results might be due to cell-type specificity, our data are consistent with the observations in other cancer cells that ERa, but not ERb, plays a predominant role in the promotion of cell growth and survival (Thomas & Gustafsson 2011). While a few reports propose the proliferative and anti-apoptotic roles of ERb in cancer cells, the tumor suppressor properties of ERb have been demonstrated by the fact that overexpression of ERb results in anti-proliferative responses, whereas knockdown of ERb promotes the proliferative properties in different cancer cell types (Treeck et al 2007, 2010, Paruthiyil et al 2011, Bossard et al 2012. Moreover, a study of 24 OSCC specimens shows that the frequency of ERa expression (50%) is higher than that of ERb expression (33%) (Lukits et al 2007).…”

Section: Discussionsupporting

confidence: 83%

Regulation of estrogen receptor α function in oral squamous cell carcinoma cells by FAK signaling

Chang¹,

Hsu²,

Wu³

et al. 2014

Endocrine-Related Cancer

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Estrogen receptor a (ERA) is a DNA-binding transcription factor that plays an important role in the regulation of cell growth. Previous studies indicated that the expression of ERa in cell lines and tumors derived from oral squamous cell carcinoma (OSCC). The aim of this study was to examine the activity and function of ERa in OSCC cells and the mechanism underlying ERa activation. Immunochemical analyses in benign (nZ11) and malignant (nZ21) lesions of the oral cavity showed that ERa immunoreactivity was observed in 43% (9/21) of malignant lesions, whereas none of benign lesions showed ERa immunoreactivity. The ERa expression was also found in three OSCC cell lines and its transcriptional activity was correlated with cell growth. Addition of estradiol stimulated cell growth, whereas treatment of tamoxifen or knockdown of ERa expression caused reduced cell growth. Interestingly, the expression and activity of focal adhesion kinase (FAK) were associated with the phosphorylation of ERa at serine 118 in OSCC cells. Elevated expression of FAK in the slow-growing SCC25 cells caused increases in ERa phosphorylation, transcriptional activity, and cell growth rate, whereas knockdown of FAK expression in the rapid-growing OECM-1 cells led to reduced ERa phosphorylation and activity and retarded cell growth. Inhibition of the activity of protein kinase B (AKT), but not ERK, abolished FAK-promoted ERa phosphorylation. These results suggest that OSCC cells expressed functional ERa, whose activity can be enhanced by FAK/AKT signaling, and this was critical for promoting cell growth. Thus, FAK and ERa can serve as the therapeutic targets for the treatment of OSCC. Key Words" oral squamous cell carcinoma " estrogen receptor a " focal adhesion kinase

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Section: Discussionsupporting

confidence: 83%

Regulation of estrogen receptor α function in oral squamous cell carcinoma cells by FAK signaling

Chang¹,

Hsu²,

Wu³

et al. 2014

Endocrine-Related Cancer

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“…In support of our study showing the tumor suppressor role of ERβ, there are emerging evidences showing that ERβ has an anti-oncogenic role in the development and progression of some tumor types, including ovarian cancer, renal cell carcinoma, prostate cancer, and colon cancers. [23][24][25][26][27][28][29] Our study and these previous reports altogether indicated a protective role of ERβ in the development and progression of cancer.…”

supporting

confidence: 58%

Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

Wei

Guo

et al. 2015

Laboratory Investigation

118

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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The incidence of HCC is strikingly higher in males than in females. The remarkable gender disparity suggests an important role for sex hormones in HCC pathogenesis. Recently, estrogen has emerged as a protective factor in the development and progression of HCC, but whether it prevents and attenuates HCC, and the mechanism of protection, have not been elucidated. The present study shows that expression of estrogen receptor (ER) β was significantly downregulated in HCC tissue compared with normal liver tissue; moreover, its expression level showed a significant negative correlation with disease progression and a positive correlation with the expression level of NLRP3 inflammasome components. In a previous study, we showed that loss of NLRP3 inflammasome in HCC tissue contributed to tumor progression, whereas the mechanism of its deregulation was not elucidated. In this study, we investigated the potential link between NLRP3 inflammasome and estrogen. Our data reveal that treatment with 17β-estradiol (E2) significantly inhibited the malignant behavior of HCC cells through E2/ERβ/ MAPK pathway-mediated upregulation of the NLRP3 inflammasome. This study shows a novel link between ERβ and the NLRP3 inflammasome in HCC progression, which provides a potentially valuable therapeutic strategy for treatment of HCC patients.

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“…Control (sh-Luc) and anti-AXL shRNAs were previously described (14). Luciferase-transfected MDA-MB-231 cells (MDA-MB-231-Luc) were previously described (16). RhGAS6 and the goat anti-human GAS6 antibody were purchased from R&D Systems.…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

“…Intraperitoneal treatments with 200 mg 20G7-D9/injection or saline were done twice a week for four consecutive weeks. Bone metastases were quantified by in vivo bioluminescence imaging at day 25, as described previously (16). For PDX models, approximately 60 mm 3 of B3804 and B3467 tumors were transplanted in the interscapular fat pads of Swiss nude female mice (Charles River Laboratories) and treated with 200 mg 20G7-D9 twice weekly or saline, when…”

Section: In Vivo Studiesmentioning

confidence: 99%

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Leconet

Chentouf

Manoir

et al. 2017

Clinical Cancer Research

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Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation.

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Potential Role of Estrogen Receptor Beta as a Tumor Suppressor of Epithelial Ovarian Cancer

Cited by 100 publications

References 55 publications

Regulation of estrogen receptor α function in oral squamous cell carcinoma cells by FAK signaling

Regulation of estrogen receptor α function in oral squamous cell carcinoma cells by FAK signaling

Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

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