Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


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


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}

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).

Read the Full Text

Post-transcriptional Regulation of Human Breast Cancer Cell Proteome by Unliganded Estrogen Receptor {beta} via microRNAs.
G. Nassa, R. Tarallo, G. Giurato, M. R. De Filippo, M. Ravo, F. Rizzo, C. Stellato, C. Ambrosino, M. Baumann, N. Lietzen, et al. (2014)
Mol. Cell. Proteomics 13, 1076-1090
   Abstract »    Full Text »    PDF »
Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice.
E. Vergadi, K. Vaporidi, E. E. Theodorakis, C. Doxaki, E. Lagoudaki, E. Ieronymaki, V. I. Alexaki, M. Helms, E. Kondili, B. Soennichsen, et al. (2014)
J. Immunol. 192, 394-406
   Abstract »    Full Text »    PDF »
Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state.
Y.-Y. Lim, J. A. Wright, J. L. Attema, P. A. Gregory, A. G. Bert, E. Smith, D. Thomas, A. F. Lopez, P. A. Drew, Y. Khew-Goodall, et al. (2013)
J. Cell Sci. 126, 2256-2266
   Abstract »    Full Text »    PDF »
PKB/Akt-Dependent Regulation of Cell Motility.
G. Xue and B. A. Hemmings (2013)
J Natl Cancer Inst 105, 393-404
   Abstract »    Full Text »    PDF »
The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets.
N. Pode-Shakked, R. Shukrun, M. Mark-Danieli, P. Tsvetkov, S. Bahar, S. Pri-Chen, R. S. Goldstein, E. Rom-Gross, Y. Mor, E. Fridman, et al. (2013)
EMBO Mol Med. 5, 18-37
   Abstract »    Full Text »    PDF »
Epithelial-mesenchymal transitions: insights from development.
J. Lim and J. P. Thiery (2012)
Development 139, 3471-3486
   Abstract »    Full Text »    PDF »
Distinct roles of AKT isoforms in regulating {beta}1-integrin activity, migration, and invasion in prostate cancer.
R. Virtakoivu, T. Pellinen, J. K. Rantala, M. Perala, and J. Ivaska (2012)
Mol. Biol. Cell 23, 3357-3369
   Abstract »    Full Text »    PDF »
MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer.
E. Aydogdu, A. Katchy, E. Tsouko, C.-Y. Lin, L.-A. Haldosen, L. Helguero, and C. Williams (2012)
Carcinogenesis 33, 1502-1511
   Abstract »    Full Text »    PDF »
Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization.
A. Arranz, C. Doxaki, E. Vergadi, Y. Martinez de la Torre, K. Vaporidi, E. D. Lagoudaki, E. Ieronymaki, A. Androulidaki, M. Venihaki, A. N. Margioris, et al. (2012)
PNAS 109, 9517-9522
   Abstract »    Full Text »    PDF »
The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY.
S. A. Ezell, C. Polytarchou, M. Hatziapostolou, A. Guo, I. Sanidas, T. Bihani, M. J. Comb, G. Sourvinos, and P. N. Tsichlis (2012)
PNAS 109, E613-E621
   Abstract »    Full Text »    PDF »
TGF-{beta}-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion.
S. Lamouille, E. Connolly, J. W. Smyth, R. J. Akhurst, and R. Derynck (2012)
J. Cell Sci. 125, 1259-1273
   Abstract »    Full Text »    PDF »
FOSL1 Is Integral to Establishing the Maternal-Fetal Interface.
L. N. Kent, M. A. K. Rumi, K. Kubota, D.-S. Lee, and M. J. Soares (2011)
Mol. Cell. Biol. 31, 4801-4813
   Abstract »    Full Text »    PDF »
Tumor Progression Locus 2 Mediates Signal-Induced Increases in Cytoplasmic Calcium and Cell Migration.
M. Hatziapostolou, G. Koukos, C. Polytarchou, F. Kottakis, O. Serebrennikova, A. Kuliopulos, and P. N. Tsichlis (2011)
Science Signaling 4, ra55
   Abstract »    Full Text »    PDF »
Angiopoietin-2, an Angiogenic Regulator, Promotes Initial Growth and Survival of Breast Cancer Metastases to the Lung through the Integrin-linked Kinase (ILK)-AKT-B Cell Lymphoma 2 (Bcl-2) Pathway.
Y. Imanishi, B. Hu, G. Xiao, X. Yao, and S.-Y. Cheng (2011)
J. Biol. Chem. 286, 29249-29260
   Abstract »    Full Text »    PDF »
Akt2 Regulates All Akt Isoforms and Promotes Resistance to Hypoxia through Induction of miR-21 upon Oxygen Deprivation.
C. Polytarchou, D. Iliopoulos, M. Hatziapostolou, F. Kottakis, I. Maroulakou, K. Struhl, and P. N. Tsichlis (2011)
Cancer Res. 71, 4720-4731
   Abstract »    Full Text »    PDF »
Nonredundant Functions for Akt Isoforms in Astrocyte Growth and Gliomagenesis in an Orthotopic Transplantation Model.
R. Endersby, X. Zhu, N. Hay, D. W. Ellison, and S. J. Baker (2011)
Cancer Res. 71, 4106-4116
   Abstract »    Full Text »    PDF »
Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion.
D. Iliopoulos, H. A. Hirsch, G. Wang, and K. Struhl (2011)
PNAS 108, 1397-1402
   Abstract »    Full Text »    PDF »
Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains.
B. Miao, I. Skidan, J. Yang, A. Lugovskoy, M. Reibarkh, K. Long, T. Brazell, K. A. Durugkar, J. Maki, C. V. Ramana, et al. (2010)
PNAS 107, 20126-20131
   Abstract »    Full Text »    PDF »
Oncogenes and Tumor Suppressor Genes.
E. Y. H. P. Lee and W. J. Muller (2010)
Cold Spring Harb Perspect Biol 2, a003236
   Abstract »    Full Text »    PDF »
The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer?.
S. Brabletz and T. Brabletz (2010)
EMBO Rep. 11, 670-677
   Abstract »    Full Text »    PDF »
Distinct Biological Roles for the Akt Family in Mammary Tumor Progression.
R. L. Dillon and W. J. Muller (2010)
Cancer Res. 70, 4260-4264
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882