Role of the CYP3A4-mediated 11,12-epoxyeicosatrienoic acid pathway in the development of tamoxifen-resistant breast cancer

Phuong, Nguyen Thi Thuy; Kim, Ji Won; Kim, Jung-Ae; Jeon, Jang Su; Lee, Ji-Yoon; Xu, Wen; Yang, Jin Won; Kim, Sang Kyum; Kang, Keon Wook

doi:10.18632/oncotarget.20329

Cited by 21 publications

(6 citation statements)

References 57 publications

(89 reference statements)

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“…However, the role of EETs in cancer is complex as these epoxyeicosanoids may stimulate pro-angiogenic and pro-tumorigenic mechanisms ( Imig & Hammock, 2009 ; Panigrahy et al, 2012 ). The CYP3A4 produced EETs play a role in breast cancer progression, including in tamoxifen-resistant subsets via proliferation, angiogenesis, and migration ( Thuy Phuong et al, 2017 ). While EETs can be mildly pro-angiogenic, inhibition of sEH prevents angiogenic diseases such as diabetic retinopathy ( Hu et al, 2017 ).…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Carcinogenesis: Failure of resolution of inflammation?

Fishbein

Hammock

Serhan

et al. 2021

Pharmacology & Therapeutics

113

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Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.

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Section: Therapeutic Approachesmentioning

confidence: 99%

Carcinogenesis: Failure of resolution of inflammation?

Fishbein

Hammock

Serhan

et al. 2021

Pharmacology & Therapeutics

113

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“…Atopaxar which is metabolized by cytochrome p450 enzyme, CYP3A4, selectively blocks protease-activated receptor-1 (PAR-1) thus preventing platelet activation by thrombin, a potent agonist and essential component of the coagulation cascade (Capodanno et al, 2013). Cytochrome p450 enzymes and PAR-1 are also expressed in breast tumors and cell lines (Yang et al, 2010; Phuong et al, 2017) and higher PAR-1 expression is related to heightened invasiveness and induction of epithelial-mesenchymal transition (Wang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Combined Anastrozole and Antiplatelet Therapy Treatment Differentially Promotes Breast Cancer Cell Survival

2020

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Thromboembolic disorders are the second leading cause of death in breast cancer. Antiplatelet therapy combined with cancer therapy is a potential treatment strategy against cancer-associated thromboembolic disorders; however, the efficacy of such dual treatment has not been established. This study reports novel findings on the response of hormone-dependent breast cancer cell lines (MCF7/T47D) following 24 h treatment with Anastrozole, combined with Aspirin and Clopidogrel cocktail; and Atopaxar. Neutral red and lactate dehydrogenase assays were conducted to assess viability and cytotoxicity respectively. Flow cytometric Annexin-V/PI assay was used to assess the mode of cell death. Morphological alterations were studied using scanning electron microscopy. Statistical analysis was conducted using Statistica V13. Definitive outcomes were established with flow cytometric detection of phosphatidylserine exposure and propidium iodide staining, complemented with ultrastructural analysis. Results showed that a few cells were undergoing death mainly through secondary necrosis. Morphological features suggesting induced cell motility (pseudopodia/ruffled membranes) were observed in both cell lines; notably, T47D cells presented pronounced features than MCF7 cells. Overall, these findings suggest that such combined treatment may differentially promote cell survival, inducing a more aggressive breast cancer phenotype.

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“…Meanwhile, HER2+ BC is found unaffected by either of the EETs. On the contrary, another study attributed the tamoxifen resistance in MDA-MB-361 (ER−/PR−/HER2+) to overexpression of CYP3A4, partly by enhancing 11,12-EET biosynthesis [ 78 ], while it is mentioned in the study by Maria Karmella Apaya that MCF-7 could not be affected by any EET [ 7 ]. Contradictory evidence reveals the existence of deeper complicated network mechanisms.…”

Section: Different Status Of Seh Mediates Epoxide Metabolism In Bcmentioning

confidence: 99%

Crosstalk between Depression and Breast Cancer via Hepatic Epoxide Metabolism: A Central Comorbidity Mechanism

Ganesan²,

Wu³

et al. 2022

Molecules

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Breast cancer (BC) is a serious global challenge, and depression is one of the risk factors and comorbidities of BC. Recently, the research on the comorbidity of BC and depression has focused on the dysfunction of the hypothalamic–pituitary–adrenal axis and the persistent stimulation of the inflammatory response. However, the further mechanisms for comorbidity remain unclear. Epoxide metabolism has been shown to have a regulatory function in the comorbid mechanism with scattered reports. Hence, this article reviews the role of epoxide metabolism in depression and BC. The comprehensive review discloses the imbalance in epoxide metabolism and its downstream effect shared by BC and depression, including overexpression of inflammation, upregulation of toxic diols, and disturbed lipid metabolism. These downstream effects are mainly involved in the construction of the breast malignancy microenvironment through liver regulation. This finding provides new clues on the mechanism of BC and depression comorbidity, suggesting in particular a potential relationship between the liver and BC, and provides potential evidence of comorbidity for subsequent studies on the pathological mechanism.

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Role of the CYP3A4-mediated 11,12-epoxyeicosatrienoic acid pathway in the development of tamoxifen-resistant breast cancer

Cited by 21 publications

References 57 publications

Carcinogenesis: Failure of resolution of inflammation?

Carcinogenesis: Failure of resolution of inflammation?

Combined Anastrozole and Antiplatelet Therapy Treatment Differentially Promotes Breast Cancer Cell Survival

Crosstalk between Depression and Breast Cancer via Hepatic Epoxide Metabolism: A Central Comorbidity Mechanism

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