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  • Original Paper
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Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis

Oncogene volume 19, pages 3460–3469 (2000)Cite this article

Abstract

The interaction between the erbB tyrosine kinase receptors and their ligands plays an important role in tumor growth via the regulation of autocrine and paracrine loops. We report the effect of heregulin β1, the ligand for erbB-3 and erbB-4 receptors, on the regulation of vascular endothelial growth factor (VEGF) expression, using a panel of breast and lung cancer cell lines with constitutive erbB-2 overexpression or engineered to stably overexpress the erbB-2 receptor. We demonstrate that heregulin β1 induces VEGF secretion in most cancer cell lines, while no significant effect was observed in normal human mammary and bronchial primary cells. Overexpression of erbB-2 receptor results in induction of the basal level of VEGF and exposure to heregulin further enhances VEGF secretion. This is associated with increased VEGF mRNA expression. In contrast, VEGF induction is significantly decreased in a T47D cell line where erbB-2 is functionally inactivated. Conditioned media from heregulin-treated cancer cells, but not from normal cells, stimulates endothelial cell proliferation; this paracrine stimulation is inhibited by co-exposure to a specific VEGF neutralizing antibody. Furthermore, heregulin-mediated angiogenesis is observed in the in vivo CAM assay. This study reports the first evidence of VEGF regulation by heregulin in cancer cells.

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Acknowledgements

We sincerely thank Dr C Kent Osborne (UT Health Science Center, San Antonio, TX, USA) for providing the MCF7-neo22 and MCF7-HER218 clones, Dr Brenda I Gerwin (National Cancer Institute, Bethesda, MD, USA) for providing the B2BN1 and B2BE6 bronchial cell lines, and Dr Ke Zhang (Amgen Inc., Thousand Oaks, CA, USA) for the HER2 expression construct (pEV7-HER2) and its control. We also thank John Cho for his helpful technical assistance. This work was supported by grant No. 011320 from the Canadian Breast Cancer Research Initiative (CBCRI), and in part by grant MT 14357 from the Medical Research Council (MRC) of Canada. MA Alaoui-Jamali is supported by a scientist salary award from the Fonds de la Recherche en Santé du Quebec (FRSQ). L Yen is supported by an FRSQ-FCAR-Santé doctoral scholarship.

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  1. Department of Medicine, Oncology, Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, H3T 1E2, Quebec, Canada

    Lily Yen, Xiao-Li You, Ala-Eddin Al Moustafa, Gerald Batist & Moulay A Alaoui-Jamali

  2. Department of Pharmacology/Therapeutics and McGill Centre for Translational Research in Cancer, McGill University, Montreal, Quebec, H3T 1E2, Canada

    Gerald Batist & Moulay A Alaoui-Jamali

  3. Friedrich Miescher-Institute, P.O. Box 2543, CH-4002, Basel, Switzerland

    Nancy E Hynes

  4. Department of Biochemistry, University of Montreal, Quebec, H3T 1P1, Canada

    Sylvie Mader

  5. Hotel Dieu de Montreal and Department of Pharmacology, Centre de Recherche, University of Montreal, Quebec, H2W 1T8, Canada

    Sylvain Meloche

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Yen, L., You, XL., Al Moustafa, AE. et al. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 19, 3460–3469 (2000). https://doi.org/10.1038/sj.onc.1203685

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