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.
Highlights
Endometrial carcinoma (EC) is a major malignant tumor of the female reproductive system [1]
OD value of HEC-1B was reduced from 0.64 to 0.34 (P < 0.001) after the pERK inhibitor treatment. These results suggested that the EGFR/ERK signaling pathway might be at the downstream of estrogen receptor (ER)/G-protein-coupled receptor-30 (GPR30) and be involved in BDE-47-induced EC cell viability
One publication by Li et al revealed that polybrominated diphenyl ethers (PBDEs)-209 increased the viability and proliferation of cells in several types of cancer, including breast cancer, cervical cancer, and ovarian cancer
Summary
Endometrial carcinoma (EC) is a major malignant tumor of the female reproductive system [1]. EC has been proposed to be classified into two pathogenetic groups, of which type I mostly occurs in pre- and peri-menopausal women with a history of unopposed estrogen exposure [4]. Studies found no difference in the positivity of estrogen receptor (ER) or progesterone receptor (PR) as well as the level of sex hormones between these two types of EC. Type II is not completely estrogen-independent [5]. Previous studies supported the role of ERα in the development of EC [4, 6]. G-protein-coupled receptor-30 (GPR30), which encodes a multi-pass membrane protein mediating the estrogen action of intracellular estrogen receptor [7, 8], has been suggested to be an indicator of EC progression [9]. The etiology and pathogenesis of EC remain poorly defined
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