Chronic BDE-47 Exposure Aggravates Malignant Phenotypes and Chemoresistance by Activating ERK Through ERα and GPR30 in Endometrial Carcinoma

Abstract

Environmental exposure to certain compounds contribute to cell plasticity, tumor progression and even chemoresistance. 2,2′,4,4′-tetrabromo diphenyl ether (BDE-47), one of the most frequently detected polybrominated diphenyl ethers (PBDEs) in environmental and biological samples, is a known estrogen disruptor closely associated with the development of hormone-dependent cancers. However, the effect of BDE-47 on endometrial carcinoma (EC), an estrogen-dependent cancer, remains to be elucidated. Mechanisms of estrogen receptor α (ERα) and G-protein-coupled receptor-30 (GPR30) involved in BDE-47 carcinogenesis are yet to be identified. This study aims to investigate the effect of BDE-47 on the invasive phenotype of estrogen-dependent EC cells. BDE-47-treated cells, such as Ishikawa-BDE-47 and HEC-1B-BDE-47 cells, exhibited increased cell viability and enhanced metastatic ability. In vivo studies showed larger tumor volumes and more metastasis in mice injected with Ishikawa-BDE-47 cells compared with parental Ishikawa cells. MTT assay showed that BDE-47 exposure could attenuate sensitivity of EC cells to cisplatin or paclitaxel treatment in vitro. Western blotting revealed overexpression of ERα, GPR30, pEGFR (phosphorylated epidermal growth factor receptor), and pERK (phosphorylated extracellular-regulated protein kinase) in Ishikawa-BDE-47 and HEC-1B-BDE-47 cells. Knockdown of ERα or GPR30 by small interfering RNA reversed the stimulating effect of BDE-47 on cell growth, migration and invasion of EC cells. Additionally, treatment with pEGFR or pERK inhibitor impaired cell viability, migration and invasion in Ishikawa-BDE-47 and HEC-1B-BDE-47 cells. Overall, our results indicate that chronic BDE-47 exposure triggers phenotypic plasticity, promotes progression and even chemoresistance in EC cells, at least in part, via ERα/GPR30 and EGFR/ERK signaling pathways.

Endocrine Disruptors and Endometrial Cancer: Molecular Mechanisms of Action and Clinical Implications, a Systematic Review

“…The so-called “legacy BFRs” are defined as obsolete, but they are still widely monitored due to their ubiquity in the environment. Zhang et al [ 27 ] evaluated the role in EC. They employed an in vitro and in vivo analysis of the effects of 2,2′, 4,4′-tetrabromo diphenyl ether (BDE-47), one of the most frequent polybrominated diphenyl ethers (PBDEs) found in environmental and biological samples.…”

“…With their estrogenic potential, it has been shown in mouse studies that NP and OP interfere with estrogenic activity with effects on the uterus resulting in endometrial proliferation [ 27 , 41 ].…”

Does G Protein-Coupled Estrogen Receptor 1 Contribute to Cisplatin-Induced Acute Kidney Injury in Male Mice?

“…Specifically, it has been recently shown that GPER1 knockdown or antagonism enhances the sensitivity of gastric cancer cells to Cp, suggesting that GPER1 can be a target to improve Cp chemotherapeutic efficacy against gastric tumors developing chemoresistance [ 69 ]. Similarly, it has been shown that exposure to the estrogen disruptor, 2,2′,4,4′-tetrabromo diphenyl ether-47 (BDE-47), attenuates the sensitivity of endometrial carcinoma cells to Cp, thus eliciting chemoresistance, at least in part via a GPER1 signaling pathway [ 70 ]. Overall, the contribution of sex hormonal receptors in the development of Cp chemoresistance is poorly understood.…”

The roles of estrogen receptor alpha (ERα) in endometrial carcinoma

“…ERα contributes to EC through the interaction with several proteins [such as DAX-1, R receptor-binding cancer antigen expressed on SiSo cells (RCAS1), etc.] and the crosstalk with some signaling pathways [such as epidermal growth factor receptor (EGFR)/ERK signaling pathway and insulin/insulin receptor signaling pathway] (Table 3) [27,[39][40][41]. For example, ERα and ERβ5 are co-expressed in the nuclei of endometrial adenocarcinoma cells, and they can form heterodimers that enhance the hormone sensitivity of Ishikawa cells, thereby promoting EC [42].…”

“…First, upstream regulators regulate the transcriptional activity of ERα and promotes the development of EC, especially in proliferation [26]. Second, ERα can promote the occurrence of EC together with co-regulators [27,28]. Third, ERα mediates EC proliferation, metastasis and apoptosis through downstream proteins or genes [29].…”