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MicroRNA-101-mediated Akt activation and estrogen-independent growth

Oncogene volume 30, pages 822–831 (2011)Cite this article

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Abstract

MicroRNAs are gene regulators that work through a posttranscriptional repression mechanism. Dysregulation of microRNA expression could lead to a variety of disorders, in particular, human cancer, and has also been implicated in antihormone therapy resistance. However, little is known whether microRNAs have a role in estrogen-independent growth, leading to tamoxifen resistance in estrogen receptor (ER)-positive tumors. In this study, we use an in vivo selection system against a microRNA library using the MCF-7 model and demonstrate that miR-101 promotes estrogen-independent growth and causes the upregulation of phosphorylated Akt (pAkt) without impacting the ER level or activity. Importantly, although miR-101 suppresses cell growth in normal estradiol (E2)-containing medium, it promotes cell growth in E2-free medium. Moreover, estrogen deprivation greatly enhances miR-101-mediated Akt activation. Finally, we show that MAGI-2 (membrane-associated guanylate kinase), a scaffold protein required for PTEN (phosphatase and tensin homolog) activity, is a direct target for miR-101; suppression of MAGI-2 by miR-101 reduces PTEN activity, leading to Akt activation. Taken together, these results not only establish a role for miR-101 in estrogen-independent signaling but also provide a mechanistic link between miR-101 and Akt activation.

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Abbreviations

ER:

estrogen receptor

PCR:

polymerase chain reaction

RT:

reverse transcription

UTR:

untranslated region

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Acknowledgements

We are grateful to Andy Wilber for the preparation of the viral stock used in this study and to Dr Yutaka Hata for the MAGI-2 construct. This work is supported by KG100027 from Susan G Komen for the Cure, by BC085629 from the Department of Defense and the research fund from Abraxis Bioscience.

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Author notes

  1. M Sachdeva and H Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA

    M Sachdeva, H Wu, P Ru & Y-Y Mo

  2. Abraxis Bioscience, Marina del Rey, CA, USA

    L Hwang & V Trieu

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  1. M Sachdeva
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  2. H Wu
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Correspondence to Y-Y Mo.

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LH and VT are employees of Abraxis Bioscience.

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Supplementary Information accompanies the paper on the Oncogene website

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Sachdeva, M., Wu, H., Ru, P. et al. MicroRNA-101-mediated Akt activation and estrogen-independent growth. Oncogene 30, 822–831 (2011). https://doi.org/10.1038/onc.2010.463

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