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Sci. Signal., 13 October 2009
Vol. 2, Issue 92, p. ra62
[DOI: 10.1126/scisignal.2000356]

RESEARCH ARTICLES

MicroRNAs Differentially Regulated by Akt Isoforms Control EMT and Stem Cell Renewal in Cancer Cells

Dimitrios Iliopoulos1*, Christos Polytarchou2*, Maria Hatziapostolou2, Filippos Kottakis2, Ioanna G. Maroulakou2, Kevin Struhl1, and Philip N. Tsichlis2{dagger}

1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2 Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.

* These authors contributed equally to this work.

Abstract: Although Akt is known to play a role in human cancer, the relative contribution of its three isoforms to oncogenesis remains to be determined. We expressed each isoform individually in an Akt1–/–/Akt2–/–/Akt3–/– cell line. MicroRNA profiling of growth factor–stimulated cells revealed unique microRNA signatures for cells with each isoform. Among the differentially regulated microRNAs, the abundance of the miR-200 family was decreased in cells bearing Akt2. Knockdown of Akt1 in transforming growth factor–β (TGFβ)–treated MCF10A cells also decreased the abundance of miR-200; however, knockdown of Akt2, or of both Akt1 and Akt2, did not. Furthermore, Akt1 knockdown in MCF10A cells promoted TGFβ-induced epithelial-mesenchymal transition (EMT) and a stem cell–like phenotype. Carcinomas developing in MMTV-cErbB2/Akt1–/– mice showed increased invasiveness because of miR-200 down-regulation. Finally, the ratio of Akt1 to Akt2 and the abundance of miR-200 and of the messenger RNA encoding E-cadherin in a set of primary and metastatic human breast cancers were consistent with the hypothesis that in many cases breast cancer metastasis may be under the control of the Akt–miR-200–E-cadherin axis. We conclude that induction of EMT is controlled by microRNAs whose abundance depends on the balance between Akt1 and Akt2 rather than on the overall activity of Akt.

{dagger} To whom correspondence should be addressed. E-mail: ptsichlis{at}tuftsmedicalcenter.org

Citation: D. Iliopoulos, C. Polytarchou, M. Hatziapostolou, F. Kottakis, I. G. Maroulakou, K. Struhl, P. N. Tsichlis, MicroRNAs Differentially Regulated by Akt Isoforms Control EMT and Stem Cell Renewal in Cancer Cells. Sci. Signal. 2, ra62 (2009).

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