The molecular mechanisms of action of the endocrine disrupting chemical bisphenol A in the development of cancer

Shafei, Ayman; Ramzy, Maggie M.; Hegazy, Abdelhares I.; Husseny, Ahmed K.; EL-hadary, Usama G.; Taha, Mazen M.; Mosa, Ali A.

doi:10.1016/j.gene.2018.01.016

Cited by 131 publications

(78 citation statements)

References 138 publications

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“…To further examine the role of ER signaling and a ceRNA mechanism in ovarian carcinogenesis, IOSE, an immortalized ovarian surface epithelial cell line, was used. First, IOSE cells were treated with the active form of estrogen, estradiol (E2), or the “environmental estrogen” bisphenol‐A (BPA), a compound known to activate ER signaling . Interestingly, treatment with E2 or BPA upregulated both E2F6 (Figure G) and c‐KIT (Figure H); IOSE cells treated with BPA and E2 for 3 days also significantly downregulated miR‐193a (Figure I).…”

Section: Resultsmentioning

confidence: 99%

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E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness

et al. 2019

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Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long‐term exposure to estrogen could increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen‐mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c‐Kit, by epigenetic silencing the tumor suppressor miR‐193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c‐KIT, but downregulated miR‐193a. Luciferase assays further confirmed that microRNA‐193a targets both E2F6 and c‐Kit. Interestingly, ChIP‐PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR‐193a, through recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, whereas E2F6 or EZH2 depletion derepressed miR‐193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR‐193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen‐mediated E2F6 ceRNA network epigenetically and competitively inhibits microRNA‐193a activity, promoting ovarian cancer stemness and tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

“…To confirm this mathematic model, in this study, we undertook biological experiments to show that E2F6 is upregulated following treatment with E2 or BPA (a “xenoestrogen”) in IOSE cells expressing miR‐193a . In addition to E2F6 upregulation, treatment with E2 or BPA also upregulated c‐KIT .…”

Section: Discussionmentioning

confidence: 98%

E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness

et al. 2019

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“…In addition, modification of proliferation and gene expression was also observed in human ovarian cancer cells when they were exposed to environmental BPA concentrations (33). Despite all this evidence, the current knowledge regarding the molecular mechanisms by which BPA acts is not enough and further studies are necessary to understand more in detail the specific signaling involved in each type of cancer since each one has its own mechanism of action (34).…”

Section: Bpa Alters Cell Proliferation Cell Death or Nutrient Supplymentioning

confidence: 99%

Endocrine disruptors from the environment affecting breast cancer (Review)

et al. 2020

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Evaluation of carcinogenic substances from the environment is a challenge for scientists. Recently, a novel approach based on 10 key characteristics of human carcinogens classified by the International Agency for Research on Cancer (IARC) has emerged. Carcinogenesis depends on different mechanisms and factors, including genetic, infectious (bacteria, viruses) and environmental (chemicals) factors. Endocrine disruptors are exogenous chemicals that can interfere and impair the function of the endocrine system due to their interaction with estrogen receptors or their estrogen signaling pathways inducing adverse effects in the normal mammary development, originating cancer. They are heterogeneous chemicals and include numerous synthetic substances used worldwide in agriculture, industry and consumer products. The most common are plasticizers, such as bisphenol A (BPA), pesticides, such as dichlorodiphenyltrichloroethane, and polychlorinated biphenyls (PCBs). Xenoestrogens appear to serve an important role in the increased incidence of breast cancer in the United States and numerous other countries. Several studies have demonstrated the role of organochlorine xenoestrogens in breast cancer. Therefore, the overall cumulative exposure of women to estrogens results in an increased risk for this type of cancer. Factors like lifestyle and diet also serve a role in the increased incidence of this disease. The aim of the present study was to analyze these chemical compounds based on the key characteristics given by the IARC, with a special focus on breast cancer, to establish whether these compounds are carcinogens, and to create a model for future analysis of other endocrine disruptors.

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“…At the mechanistic level, a large number of in vivo and in vitro studies have highlighted the ability of BPA to disrupt several key signaling pathways that are known to be involved in breast cancer [19,40]. However, the direct involvement of BPA in breast cancer incidence is difficult to establish and remains controversial [26,41], owing possibly to the fact that different mechanisms are depicted in either ER-positive or -negative tumors, reflecting the variety of biological effects arising from exposure to BPA [20,28,42]. In addition, the combinatorial effects of different pollutants encountered over a life time also complicate these studies.…”

Section: Bpa Involvement In Breast Cancermentioning

confidence: 99%

A Potential New Mechanism for Bisphenol Molecules to Initiate Breast Cancer through Alteration of Bone Morphogenetic Protein Signaling in Stem Cells and Their Microenvironment

Guyot¹,

Maguer-Satta²

2020

Breast Cancer Biology

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Endocrine disruptors interfere with endocrine-mediated regulations of cell or organ functions. Estrogens are one of the main hormones altered by endocrine disruptors like bisphenol A (BPA). Stem cells are active from embryogenesis to late stages of adult life. Their unique properties, such as an extended lifespan and low cycling features, render these cell privileged targets of long-term exposure to numerous factors. Therefore, stem cells are likely to be affected following exposure to endocrine disruptors. One of the major signaling pathways involved in stem cell regulation is the bone morphogenetic protein (BMP) pathway. The BMP pathway is known for its involvement in numerous physiological and pathophysiological processes. Exposure of human mammary stem cells to pollutants such as BPA initiates fundamental changes in stem cells, in particular by altering major elements of BMP signaling, such as receptor expression and localization. Lastly, BPA and its substitute bisphenol S (BPS) have similar impacts on BMP signaling despite their different ER-binding properties, supporting the hypothesis that their biological effects cannot be extrapolated only from their interaction with ERα66. We review recent discoveries in this field and discuss their implications for cancer diagnosis, prevention, and treatment, as well as their relevance for studies on endocrine disruptors.

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The molecular mechanisms of action of the endocrine disrupting chemical bisphenol A in the development of cancer

Cited by 131 publications

References 138 publications

E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness

E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness

Endocrine disruptors from the environment affecting breast cancer (Review)

A Potential New Mechanism for Bisphenol Molecules to Initiate Breast Cancer through Alteration of Bone Morphogenetic Protein Signaling in Stem Cells and Their Microenvironment

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