Bisphenol A induces proliferative effects on both breast cancer cells and vascular endothelial cells through a shared GPER-dependent pathway in hypoxia

Xu, Fangyi; Wang, Xiaoning; Wu, Nannan; He, Siyu; Wu, Yi; Xiang, Siyun; Zhang, Piwei; Xie, Xia; Ying, Chenjiang

doi:10.1016/j.envpol.2017.09.069

Cited by 56 publications

(48 citation statements)

References 56 publications

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“…Widespread exposure to bisphenol compounds (BPA and BPS) of humans occurs through the oral, dermal, and inhalation routes. Low dosages of BPA/BPS might trigger a proliferative effect in various cell types, as has been shown for cells of the pancreatic islets (Carchia et al 2015;Wei et al 2017), endothelium (Xu et al 2017), and breast after developmental treatment of mice with BPA (Acevedo et al 2013) and cells of the pituitary gland of zebrafish treated with BPS (Ji et al 2013) and a rat pituitary cell line after BPS treatment (Viñas and Watson 2013).…”

Section: Tet2-mediated Dna Hydroxymethylation Represses Bisphenol-stimentioning

confidence: 80%

Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

Lyu

Ren

et al. 2020

Environ Health Perspect

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BACKGROUND: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor targeting estrogen receptors (ERs), has been implicated in the promotion of breast cancer. Perinatal exposure of BPA could induce longitudinal alteration of DNA hydroxymethylation in imprinted loci of mouse blood cells. To date, no data has been reported on the effects of BPA on DNA hydroxymethylation in breast cells. Therefore, we asked whether BPA can induce DNA hydroxymethylation change in human breast cells. Given that dysregulated epigenetic DNA hydroxymethylation is observed in various cancers, we wondered how DNA hydroxymethylation modulates cancer development, and specifically, whether and how BPA and its analogs promote breast cancer development via DNA hydroxymethylation. OBJECTIVES: We aimed to explore the interplay of the estrogenic activity of bisphenols at environmental exposure dose levels with TET dioxygenase-catalyzed DNA hydroxymethylation and to elucidate their roles in the proliferation of ER + breast cancer cells as stimulated by environmentally relevant bisphenols. METHODS: Human MCF-7 and T47D cell lines were used as ER-dependent breast cell proliferation models, and the human MDA-MB-231 cell line was used as an ER-independent breast cell model. These cells were treated with BPA or bisphenol S (BPS) to examine BPA/BPS-related proliferation. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and enzyme-linked immunosorbent assays (ELISAs) were used to detect DNA hydroxymethylation. Crispr/Cas9 and RNA interference technologies, quantitative polymerase chain reaction (qPCR), and Western blot analyses were used to evaluate the expression and function of genes. Co-immunoprecipitation (Co-IP), bisulfite sequencing-PCR (BSP), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to identify the interactions of target proteins. RESULTS: We measured higher proliferation in ER + breast cancer cells treated with BPA or its replacement, BPS, accompanied by an ERa-dependent decrease in genomic DNA hydroxymethylation. The results of our overexpression, knockout, knockdown, and inhibition experiments suggested that TET2-catalyzed DNA hydroxymethylation played a suppressive role in BPA/BPS-stimulated cell proliferation. On the other hand, we observed that TET2 was negatively regulated by the activation of ERa (dimerized and phosphorylated), which was also induced by BPA/BPS binding. Instead of a direct interaction between TET2 and ERa, data of our Co-IP, BSP, and ChIP-qPCR experiments indicated that the activated ERa increased the DNA methyltransferase (DNMT)-mediated promoter methylation of TET2, leading to an inhibition of the TET2 expression and DNA hydroxymethylation. CONCLUSIONS: We identified a new feedback circuit of ERa activation-DNMT-TET2-DNA hydroxymethylation in ER + breast cancer cells and uncovered a pivotal role of TET2-mediated DNA hydroxymethylation in modulating BPA/BPS-stimulated proliferation. Moreover, to our knowledge, we for the first time established a linkage among...

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Section: Tet2-mediated Dna Hydroxymethylation Represses Bisphenol-stimentioning

confidence: 80%

Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

Lyu

Ren

et al. 2020

Environ Health Perspect

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“…Evidence for a stimulatory role exerted by E2-activated GPER on HIF-1α expression was obtained also in certain physio-pathological conditions associated with de-regulated estrogen signaling as endometriosis [ 197 ]. Recently, Xu et al demonstrated that in a hypoxic microenvironment, BPA promotes proliferative effects in both breast cancer cell and endothelial cells by inducing HIF-1α and VEGF expressions in a GPER-mediated manner [ 198 ]. These data suggest that a molecular loop connecting HIF-1α and GPER supports breast cancer progression in a multilayered fashion that includes components of both cancer and stromal cells.…”

Section: Hif-1α Regulation By E2 (Er E Gper)mentioning

confidence: 99%

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT

Francesco

Maggiolini

Musti

2018

IJMS

114

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The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell–cell adhesion and apical–basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression.

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“…This model for Ppa-NHR-40 function would show resemblance to the related human receptor HNF4α, which activates the transcription of the cytosolic sulfotransferase SULT1E1 (Kodama et al, 2011). However, the role of bisphenol A would remain unclear in this model, because bisphenol A is known from other systems to be inactivated by sulfotransferases, and acts as xenobiotic ligand of mammalian nuclear hormone receptors, such as the estrogen receptor during breast cancer formation (Kodama and Negishi, 2015;Sui et al, 2012;Xu et al, 2017).…”

Section: Sult-1 and Eud-1 Exhibit Distinct Expression Profilesmentioning

confidence: 99%

Two independent sulfation processes regulate mouth-form plasticity in the nematodePristionchus pacificus

et al. 2018

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Sulfation of biomolecules, like phosphorylation, is one of the most fundamental and ubiquitous biochemical modifications with important functions during detoxification. This process is reversible, involving two enzyme classes: a sulfotransferase, which adds a sulfo group to a substrate; and a sulfatase that removes the sulfo group. However, unlike phosphorylation, the role of sulfation in organismal development is poorly understood. In this study, we find that two independent sulfation events regulate the development of mouth morphology in the nematode This nematode has the ability to form two alternative mouth morphologies depending on environmental cues, an example of phenotypic plasticity. We found that, in addition to a previously described sulfatase, a sulfotransferase is involved in regulating the mouth-form dimorphism in However, it is unlikely that both of these sulfation-associated enzymes act upon the same substrates, as they are expressed in different cell types. Furthermore, animals mutant in genes encoding both enzymes show condition-dependent epistatic interactions. Thus, our study highlights the role of sulfation-associated enzymes in phenotypic plasticity of mouth structures in

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Bisphenol A induces proliferative effects on both breast cancer cells and vascular endothelial cells through a shared GPER-dependent pathway in hypoxia

Cited by 56 publications

References 56 publications

Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT

Two independent sulfation processes regulate mouth-form plasticity in the nematodePristionchus pacificus

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