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Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

Oncogene volume 30, pages 3084–3095 (2011)Cite this article

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Abstract

The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

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Acknowledgements

We thank Drs Isselbacher, Haber, Engelman and Zou for critically reading the paper. This work was supported by the NIH/NCI Grant CA89138 (to SM), the Susan G Komen for the Cure Grants PDF0600282 and KG090412 (to SM) and ESSCO breast cancer research grant (to SM).

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Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    F Takahashi, N Chiba, K Tajima, T Hayashida, T Shimada, M Takahashi & S Maheswaran

  2. Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    F Takahashi, N Chiba, K Tajima, T Hayashida, T Shimada, M Takahashi, E J Edelman, S Ramaswamy & S Maheswaran

  3. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    H Moriyama

  4. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    E Brachtel

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  1. F Takahashi
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Takahashi, F., Chiba, N., Tajima, K. et al. Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib. Oncogene 30, 3084–3095 (2011). https://doi.org/10.1038/onc.2011.24

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