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HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells

Oncogene volume 26, pages 3998–4008 (2007)Cite this article

Abstract

Expression of homeobox A1 (HOXA1) results in oncogenic transformation of immortalized human mammary epithelial cells with aggressive tumor formation in vivo. However, the mechanisms by which HOXA1 mediates oncogenic transformation is not well defined. To identify molecules that could potentially be involved in HOXA1-mediated oncogenic transformation, microarray analysis was utilized to characterize and compare the gene expression pattern in response to forced expression or depletion of HOXA1 in human mammary carcinoma cells. Gene expression profiling identified that genes involved in the p44/42 mitogen-activated protein (MAP) kinase activation pathway (GRB2, MAP kinase kinase (MEK1) and SDFR1) or p44/42 MAP kinase-regulated genes (IER3, EPAS1, PCNA and catalase) are downstream expression targets of HOXA1. Forced expression of HOXA1 increased GRB2 and MEK1 mRNA and protein expression and increased p44/42 MAP kinase phosphorylation, activity and Elk-1-mediated transcription. Use of a MEK1 inhibitor demonstrated that increased p44/42 MAP kinase activity is required for the HOXA1-mediated increase in cell proliferation, survival, oncogenicity and oncogenic transformation. Thus, modulation of the p44/42 MAP kinase pathway is one mechanism by which HOXA1 mediates oncogenic transformation of the human mammary epithelial cell.

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Author notes

  1. K M Mohankumar and X Q Xu: Both these authors contributed equally to this work.

Authors and Affiliations

  1. The Liggins Institute and National Research Centre for Growth and Development, University of Auckland, Auckland, New Zealand

    K M Mohankumar, N Kannan, P D Gluckman, B S Emerald & P E Lobie

  2. Microarray and Expression Genomics, Genome Institute of Singapore, Singapore, Republic of Singapore

    X Q Xu, L D Miller & E T Liu

  3. Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    T Zhu & S Sukumar

Authors
  1. K M Mohankumar
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  2. X Q Xu
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  3. T Zhu
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  4. N Kannan
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  5. L D Miller
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  6. E T Liu
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  7. P D Gluckman
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  8. S Sukumar
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  9. B S Emerald
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  10. P E Lobie
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Corresponding author

Correspondence to P E Lobie.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Mohankumar, K., Xu, X., Zhu, T. et al. HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells. Oncogene 26, 3998–4008 (2007). https://doi.org/10.1038/sj.onc.1210180

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