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Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis

Oncogene volume 30, pages 2836–2845 (2011)Cite this article

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Abstract

The major heat shock protein Hsp72 is expressed at elevated levels in many human cancers and its expression correlates with tumor progression. Here, we investigated the role of Hsp72 in Her2 oncogene-induced neoplastic transformation and tumorigenesis. Expression of Her2 in untransformed MCF10A mammary epithelial cells caused transformation, as judged by foci formation in culture and tumorigenesis in xenografts. However, expression of Her2 in Hsp72-depleted cells failed to induce transformation. The anti-tumorigenic effects of Hsp72 downregulation were associated with cellular senescence because of accumulation of p21 and depletion of survivin. Accordingly, either knockdown of p21 or expression of survivin reversed this senescence process. Further, we developed an animal model of Hsp72-dependent breast cancer associated with expression of Her2. Knockout (KO) of Hsp72 almost completely suppressed tumorigenesis in the MMTVneu breast cancer mouse model. In young Hsp72 KO mice, expression of Her2 instead of mammary tissue hyperplasia led to suppression of duct development and blocked alveolar budding. These effects were due to massive cell senescence in mammary tissue, which was associated with upregulation of p21 and downregulation of survivin. Therefore, Hsp72 has an essential role in Her2-induced tumorigenesis by regulating oncogene-induced senescence pathways.

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Acknowledgements

This work was supported by grants from the National Institute of Health CA081244. We thank Dr B Park and Dr C Spangenberg for their kind supply of MCF10A cells and HER2-overexpressing retroviral vector.

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Authors and Affiliations

  1. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

    L Meng, J A Yaglom, V L Gabai & M Y Sherman

  2. Department of Radiation Oncology, Washington University, St Louis, MO, USA

    C Hunt

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  1. L Meng
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  2. C Hunt
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  3. J A Yaglom
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  4. V L Gabai
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  5. M Y Sherman
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Correspondence to V L Gabai or M Y Sherman.

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Meng, L., Hunt, C., Yaglom, J. et al. Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis. Oncogene 30, 2836–2845 (2011). https://doi.org/10.1038/onc.2011.5

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