Altered Death Receptor Signaling Promotes Epithelial-to-Mesenchymal Transition and Acquired Chemoresistance

Antoon, James W.; Lai, Rongye; Struckhoff, Amanda P.; Nitschke, Ashley; Elliott, Steven; Martin, Elizabeth C.; Rhodes, Lyndsay V.; Yoon, Nam Seung; Salvo, Virgilio A.; Shan, Bin; Beckman, Barbara S.; Nephew, Kenneth P.; Burow, Matthew E.

doi:10.1038/srep00539

Cited by 33 publications

(38 citation statements)

References 61 publications

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“…This shift to a more mesenchymal phenotype fits with the current literature suggesting that drug treatment can effect cellular behaviour and plasticity, with EMT linked to chemoresistance in a number of cell lines and tumour types, including breast cancer [22,44-46]. …”

Section: Discussionsupporting

confidence: 85%

The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

et al. 2013

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BackgroundAcquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically.MethodsAn in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays.ResultsTamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT.ConclusionsThese data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt signalling inhibits the effects of Tamoxifen should be undertaken. As a number of small molecules targeting the Wnt pathway are currently in pre-clinical development, combinatorial treatment with endocrine agents and Wnt pathway inhibitors may be a useful therapeutic option in the future for a subset of breast cancer patients.

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Section: Discussionsupporting

confidence: 85%

The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

et al. 2013

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“…Recent studies have shown that an ETS1-mediated transcription of members of the MMP family is responsible for remodelling of the extracellular matrix in both angiogenesis and invasion [48]. Resistance to TNF-α promotes tumourigenesis [49, 50], and elevated miR-221 may have a role in mediating these effects via its suppression of ETS1 [51]. Thus, chronic upregulation of miR-221 in obesity may potentially increase cancer risk.…”

Section: Discussionmentioning

confidence: 99%

Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α

et al. 2013

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Aims/hypothesisMicroRNAs (miRNAs) are short endogenous RNAs that regulate multiple biological processes including adipogenesis and fat metabolism. We sought to identify miRNAs that correlate with BMI and to elucidate their upstream regulation and downstream targets.MethodsMicroarray-based expression profiling of 233 miRNAs was performed on subcutaneous abdominal adipose tissue biopsies from 29 non-diabetic Pima Indian participants. Correlation of the expression levels of eight miRNAs with BMI was assessed by quantitative reverse transcription (QRT) PCR in adipose samples from 80 non-diabetic Pima Indians with a BMI of 21.6–54.0 kg/m2. The upstream regulation of one of these miRNAs, miR-221, was tested by treating cultured human pre-adipocytes with leptin, TNF-α and insulin. Predicted targets of miR-221 were validated using QRT-PCR, immunoblots and luciferase assays. The downstream effects of miR-221 overexpression were assayed by proteomic analysis.ResultsExpression levels of miR-221 were positively correlated with BMI (particularly in women) and fasting insulin concentrations, while the levels of miR-193a-3p and miR-193b-5p were negatively correlated with BMI; other miRNAs did not show significant associations in the 80 samples. miR-221 was downregulated by leptin and TNF-α treatment in cultured human pre-adipocytes. Conversely, miR-221 overexpression upregulated several proteins involved in fat metabolism, mimicking peroxisome proliferator-activated receptor (PPAR) activation. Furthermore, miR-221 directly downregulated the adiponectin receptor 1 (ADIPOR1) and the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1). Adiponectin signalling is known to promote insulin sensitivity, and ETS1 is crucial for angiogenesis.Conclusions/interpretationOur data suggest that miR-221 may contribute to the development of the insulin resistance that typically accompanies obesity, by affecting PPAR signalling pathways and by directly downregulating ADIPOR1 and ETS1.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-2950-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…To investigate mechanisms by which cancer cells progress to a resistant phenotype, we employed a previously established in vitro model of acquired resistance (27,35,37,39,83), the cell line MCF-7TN-R, which is resistant to both death receptors and chemotherapeutic drugs that depend on p38 MAPK and NF-κB signaling (27,37,55,84). Further, we investigated whether progression to apoptotic resistance also associated with increased hormone-independent tumor formation and p38 signaling.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

Antoon

Nitzchke

Martin

et al. 2013

International Journal of Oncology

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Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF-κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N-cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR-200, miR-303, miR-302, miR-199 and miR-328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.

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Altered Death Receptor Signaling Promotes Epithelial-to-Mesenchymal Transition and Acquired Chemoresistance

Cited by 33 publications

References 61 publications

The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α

Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

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