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Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators

Oncogene volume 29, pages 3335–3348 (2010)Cite this article

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Abstract

Activating mutations in the tyrosine kinase domain of HER2 (ErbB2) have been identified in human cancers. Compared with wild-type HER2, mutant HER2 shows constitutively activate kinase activity and increased oncogenicity. Cells transformed by mutant HER2 are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and exhibit an attenuated response to the HER2 antibody trastuzumab. We investigated herein pathways through which mutant HER2 alters the extracellular environment, potentially leading to drug resistance and the effect of simultaneously targeting HER2 and the tumor cell microenvironment with a therapeutic intent. Expression of mutant HER2 in mammary epithelial cells activated autocrine transforming growth factor (TGF) β1 signaling through a mechanism involving Rac1 and c-Jun N-terminal kinase-activating protein 1-dependent transcription. Cells transformed by an activating mutant of H-Ras (G12V) also expressed higher TGF-β1 level through Rac1 activation. In addition, mutant HER2 induced the EGFR ligands TGF-α and amphiregulin at the mRNA and protein levels. Vascular endothelial growth factor, a target of the TGF-β-Smad transcriptional regulation, was also induced as a result of expression of mutant HER2. Inhibition of TGF-β signaling with the Alk5 small molecule inhibitor LY2109761 reduced growth and invasiveness of cells expressing mutant HER2. Combined inhibition of intracellular and paracrine effects of mutant HER2 by trastuzumab and the EGFR antibody cetuximab were more efficient than single-agent therapies. These data suggest that mutations in oncogenes such as HER2 and Ras not only alter intracellular signaling but also influence on other components of the tumor microenvironment by inducing several pro-invasive growth factors. In turn, these serve as extracellular targets of novel therapeutic strategies directed at both cancer-driving oncogenes and the modified tumor microenvironment.

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Acknowledgements

This work was supported by NCI K99/R00 CA125892 (SEW), NCI R01 CA62212 (CLA), R01 CA80195 (CLA), ACS Clinical Research Professorship Grant CRP-07-234 (CLA), Breast Cancer Specialized Program of Research Excellence (SPORE) P50 CA98131, and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant P30 CA68485.

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Authors and Affiliations

  1. Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA

    S E Wang

  2. Department of Immunology and Biotherapy, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, PR, China

    Y Yu & X Ren

  3. Department of Cancer Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    T L Criswell, L M DeBusk, P C Lin, R Zent & C L Arteaga

  4. Department of Radiation Oncology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    L M DeBusk & P C Lin

  5. Department of Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    R Zent, D H Johnson & C L Arteaga

  6. Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    C L Arteaga

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  1. S E Wang
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Correspondence to S E Wang or C L Arteaga.

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Wang, S., Yu, Y., Criswell, T. et al. Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators. Oncogene 29, 3335–3348 (2010). https://doi.org/10.1038/onc.2010.112

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