Global microRNA level regulation of EGFR‐driven cell‐cycle protein network in breast cancer

Uhlmann, Stefan; Mannsperger, Heiko; Zhang, Jitao David; Horvát, Emőke-Ágnes; Schmidt, Christian; Küblbeck, Moritz; Henjes, Frauke; Ward, Adrian; Tschulena, Ulrich; Zweig, Katharina Anna; Korf, Ulrike; Wiemann, Stefan; Şahin, Özgür

doi:10.1038/msb.2011.100

Cited by 187 publications

(179 citation statements)

References 42 publications

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“…These results suggest that miR-193a-3p may be involved in the pathogenesis of lung cancer as a tumor suppressor. Indeed, miR193a-3p has been reported in many studies to be down-regulated in cancers (31,33,38,52,54,55). On the other hand, it is well known that a single miRNA can target multiple genes, whereas multiple miRNAs can target a single gene.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of miR193a-3p has been reported in various types of cancer, such as NSCLC (29), prostate cancer (30), breast cancer (31), head and neck squamous cell carcinoma (32), colorectal cancer (33), myeloid leukemia (34), and Wilms tumor (35). The carcinogenic impact of miR-193a-3p has been attributed to its repression of c-Kit (34) and the PTEN/PI3K signaling pathway in acute myeloid leukemia (34); of KRAS and PLAU in colon cancer (36); of PLAU (37) and EGFR-driven cell cycle network proteins (38) in breast cancer; of ARHGAP19, CCND1, ERBB4, KRAS, and Mcl-1 in epithelial ovarian cancer (39); of PLAU in hepatocellular carcinoma (40); and of Mcl-1 in NSCLC (41). Thus, miR-193a-3p functions as a tumor suppressor in human cancers.…”

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confidence: 99%

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miR-193a-3p Functions as a Tumor Suppressor in Lung Cancer by Down-regulating ERBB4

Liang

Liu

Yan

et al. 2015

Journal of Biological Chemistry

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Background: ERBB4 plays an important role in the etiology and progression of lung cancer. Results: miR-193a-3p suppressed proliferation and invasion and promoted apoptosis in lung cancer cells and xenograft mice by negatively regulating ERBB4. Conclusion: miR-193a-3p exerted an anti-tumor effect by negatively regulating ERBB4 in lung cancer. Significance:This study may open new avenues for future lung cancer therapies.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

miR-193a-3p Functions as a Tumor Suppressor in Lung Cancer by Down-regulating ERBB4

Liang

Liu

Yan

et al. 2015

Journal of Biological Chemistry

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“…Compared with treatment based on small interfering RNAs (siRNAs), each of which can only silence one gene, the use of miRNAs as treatment agents seems much more beneficial. For example, multiple genes in the EGFR signalling pathway, including MAPK, STAT3 and AKT2, are all potential targets of miR-124 [166].…”

Section: Mirnas As Therapeutic Agents In Nsclc Treatmentmentioning

confidence: 99%

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Florczuk¹,

Szpechcinski²,

Chorostowska‐Wynimko³

2017

Targ Oncol

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Lung cancer is the most common cancer worldwide. Up to 85% of lung cancer cases are diagnosed as nonsmall cell lung cancer (NSCLC). The effectiveness of NSCLC treatment is expected to be improved through the implementation of robust and specific biomarkers. MicroRNAs (miRNAs) are small, non-coding molecules that play a key role in the regulation of basic cellular processes, including differentiation, proliferation and apoptosis, by controlling gene expression at the post-transcriptional level.

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“…Western blot was done as previously described [14,39]. List of antibodies used in this study is given in Supplementary information, Table S4.…”

Section: Western Blot and Immunoprecipitationmentioning

confidence: 99%

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

et al. 2014

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Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/ trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors bypassed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.

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Global microRNA level regulation of EGFR‐driven cell‐cycle protein network in breast cancer

Abstract: A genome-wide microRNA (miRNome) screen coupled with high-throughput monitoring of protein levels reveals complex, modular miRNA regulation of the EGFR-driven cell-cycle network, and identifies new miRNAs that can suppress breast cancer cell proliferation.

Cited by 187 publications

References 42 publications

miR-193a-3p Functions as a Tumor Suppressor in Lung Cancer by Down-regulating ERBB4

miR-193a-3p Functions as a Tumor Suppressor in Lung Cancer by Down-regulating ERBB4

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

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