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HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Oncogene volume 25, pages 6986–6996 (2006)Cite this article

Abstract

We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin®) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro- and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

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Acknowledgements

We sincerely thank Dr Maureen Goode for critical review of this manuscript; Dr José Baselga (Vall d'Hebron University Hospital, Barcelona, Spain) for providing the BT474 cells used in the xenografts experiments. We are also grateful to Genentech Corp (South San Francisco, CA) for providing trastuzumab (Herceptin®) and 4D5 antibodies. Dr Han Jiahuai at Scripps Research Institute, La Jolla, CA, generously provided the MKK6 vector. The Media Preparation Core Facility and Animal Core Facility were supported in part by the Cancer Center Support Grant CA No. 16672 from NCI. This work was supported in part by grant CA39930 from the National Cancer Institute (to RCB) and by grant 80094241 from Goodwin Foundation (to XFL).

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Authors and Affiliations

  1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X-F Wen, W Mao, R C Bast Jr & X-F Le

  2. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Yang & J Liu

  3. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Thornton

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  1. X-F Wen
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Correspondence to R C Bast Jr or X-F Le.

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Wen, XF., Yang, G., Mao, W. et al. HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. Oncogene 25, 6986–6996 (2006). https://doi.org/10.1038/sj.onc.1209685

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