Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

Oliveras‐Ferraros, Cristina; Corominas-Faja, Bruna; Cufí, Sílvia; Vázquez-Martín, Alejandro; Martín-Castillo, Begoña; Iglesias, Juan Manuel; López-Bonet, Eugeni; Martín, Ángel G.; Menendez, Javier A.

doi:10.4161/cc.22225

Cited by 125 publications

(113 citation statements)

References 84 publications

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“…8 The expression of some genes during the execution of the EMT process can interfere with tumor sensitivity to chemotherapeutic treatment. 44 During EMT, the expression of miR200s is downregulated by ZEB1, Snail, and Slug (SNAI2) in tumors of epithelial origin. 45 On the other hand, miR200s expression is necessary at the metastasis site to regain the epithelial phenotype and to target the expression of SEC23A, which mediates secretion Figure 6.…”

Section: Resultsmentioning

confidence: 99%

Activation of miR200 by c-Myb depends on ZEB1 expression and miR200 promoter methylation

et al. 2013

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RepoRt tumor progression to metastasis is a complex, sequential process that requires proliferation, resistance to apoptosis, motility and invasion to colonize at distant sites. the acquisition of these features implies a phenotypic plasticity by tumor cells that must adapt to different conditions by modulating several signaling pathways 1 during the journey to the final site of metastasis. Several transcription factors and microRNA play a role in tumor progression, but less is known about the control of their expression during this process. Here, we demonstrate by ectopic expression and gene silencing that the proto-oncogene c-Myb activates the expression of the five members of miR200 family (miR200b, miR200a, miR429, miR200c and miR141) that are involved in the control of epithelial-mesenchymal transition (eMt) and metastasis in many types of cancers. transcriptional activation of miR200 by c-Myb occurs through binding to myb binding sites located in the promoter regions of miR200 genes on human chromosomes 1 and 12. Furthermore, when c-Myb and the transcriptional repressor ZeB1 are co-expressed, as at the onset eMt, the repression by ZeB1 prevails over the activation by c-Myb, and the expression of miR200 is inhibited. We also demonstrate that during eMt induced by tGF-b, the promoters of miR200 genes are methylated, and their transcription is repressed regardless of the presence of repressors such as ZeB1 and activators such as c-Myb. Finally, we find a correlation between the expression of c-Myb and that of four out of five miR200 in a data set of 207 breast cancer patients.

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Section: Resultsmentioning

confidence: 99%

Activation of miR200 by c-Myb depends on ZEB1 expression and miR200 promoter methylation

et al. 2013

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“…That metformin could not entirely restore the abundance of H3K27me3 occurring in the liver of HFD‐fed animals (Vella et al., 2013) might reflect the epigenetic incapacity of HFD‐damaged tissues to fully benefit from the expected response to metformin unless combined with diet reversal (Riera‐Borrull et al., 2017). At a dose of 250 mg kg −1 day −1 i.p., a route of administration that is equivalent to 1,200 mg/day metformin for a 60 kg individual (Reagan‐Shaw, Nihal & Ahmad, 2008) and yields plasma concentrations in the low micromolar range (Chandel et al., 2016; Dowling et al., 2016; Memmott et al., 2010; Menendez, Martin‐Castillo & Joven, 2016), metformin treatment resulted in a significant twofold reduction in the tumor volume in xenograft‐bearing mice highly enriched with tumor‐initiating cancer stem cells (CSC) (Cufi et al., 2012; Martin‐Castillo et al., 2013; Oliveras‐Ferraros et al., 2012) that was accompanied by a noteworthy twofold augmentation of global H3K27me3 in tumor tissues. Because decreased abundance of H3K27me3 is a predictor of cancer aggressiveness independently of the expression of the H3K27me3 methyltransferase EZH2 (Holm et al., 2012; Wei et al., 2008) closely related to the maintenance of poorly differentiated CSC (Sakaki et al., 2015; Yan et al., 2017), our findings suggest that metformin might exert a suppressive influence on the CSC phenotype by enhancing deposition of the repressive H3K27me3 mark.…”

Section: Discussionmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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“…þ breast cancer cells with high expression of the EMT markers Slug and Snail displayed intrinsic resistance toward the HER2-targeting antibody trastuzumab, which was reverted by knockdown of these transcription factors (25). Also, loss of MED12, which conferred resistance in several tumor types to multiple targeted therapies, including EGFR and MEK inhibitors, was shown to induce a partial EMT (26).…”

Section: Epithelial-to-mesenchymal Transition Induces Resistance To Tmentioning

confidence: 99%

Phenotype Switching: Tumor Cell Plasticity as a Resistance Mechanism and Target for Therapy

et al. 2014

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Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape route. By switching from a proliferative to an invasive state, melanoma cells can acquire resistance to these targeted therapeutics. Interestingly, phenotype switching bears a striking resemblance to the epithelial-to-mesenchymal-like transition that has been described to occur in cancer stem cells in other tumor types. We propose that these changes are manifestations of one and the same underlying feature, namely a dynamic and reversible phenotypic tumor cell plasticity that renders a proportion of cells both more invasive and resistant to therapy. At the same time, the specific characteristics of these tumor cell populations offer potential for being explored as target for therapeutic intervention. Cancer Res; 74(21); 5937-41. Ó2014 AACR.

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Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

Cited by 125 publications

References 84 publications

Activation of miR200 by c-Myb depends on ZEB1 expression and miR200 promoter methylation

Activation of miR200 by c-Myb depends on ZEB1 expression and miR200 promoter methylation

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Phenotype Switching: Tumor Cell Plasticity as a Resistance Mechanism and Target for Therapy

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