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HER2/neu increases the expression of Wilms' Tumor 1 (WT1) protein to stimulate S-phase proliferation and inhibit apoptosis in breast cancer cells

Oncogene volume 24, pages 1648–1652 (2005)Cite this article

Abstract

High levels of the Wilms' Tumor 1 (WT1) protein and mRNA had been associated with aggressive phenotypes of breast tumors. Here we report that the HER2/neu oncogene increases WT1 expression. Approximately threefold higher levels of WT1 protein were observed in MCF-7 breast cancer cells transfected with the HER2/neu oncogene than in parental MCF-7 cells. Conversely, inhibition of HER2/neu with the anti-HER2/neu trastuzumab (Herceptin™) antibody decreased WT1 protein levels in HER2/neu-overexpressing BT-474 and SKBr3 cells. We also found that HER2/neu engages Akt to regulate WT1 levels since inhibition of Akt reduced WT1 levels. Decreased expression of WT1 protein led to cell cycle arrest at the G1 phase and increased apoptosis in HER2/neu-overexpressing cells, which is correlated with decreased cyclin D1 and Bcl-2 levels. Our data indicate that HER2/neu engages Akt to increase WT1 expression, and that WT1 protein plays a vital role in regulating cell cycle progression and apoptosis in HER2/neu-overexpressing breast cancer cells.

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Acknowledgements

This work was supported by the US Department of the Army DAMD 17-02-1-0459 (to AMT). The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. The research described herein does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. We thank Karen M Ramirez and The University of Texas MD Anderson Cancer Center Department of Immunology Flow Cytometry Core Lab for their technical assistance.

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  1. Department of Experimental Therapeutics, Unit 422, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, USA

    Musaffe Tuna, Arturo Chavez-Reyes & Ana M Tari

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  1. Musaffe Tuna
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  3. Ana M Tari
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Correspondence to Ana M Tari.

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Tuna, M., Chavez-Reyes, A. & Tari, A. HER2/neu increases the expression of Wilms' Tumor 1 (WT1) protein to stimulate S-phase proliferation and inhibit apoptosis in breast cancer cells. Oncogene 24, 1648–1652 (2005). https://doi.org/10.1038/sj.onc.1208345

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