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Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells

Oncogene volume 19, pages 6271–6276 (2000)Cite this article

Abstract

ErbB2 can be activated by its own overexpression or be transactivated by the heregulin polypeptide growth factor. Activation of ErbB2 leads to breast cancer cell proliferation, presumably by inducing the activation of extracellular signal-regulated kinases 1,2 (Erk1,2) and Akt. We have previously reported that the growth factor receptor bound protein-2 (Grb2) is required for the proliferation of ErbB2-overexpressing breast cancer cells. We investigated here whether Grb2 protein plays a role in heregulin-stimulated proliferation. Grb2 protein inhibition led to growth inhibition of heregulin-stimulated breast cancer cells, but not Erk1,2 inactivation. These findings are similar to our earlier observations in ErbB2-overexpressing cells. Since Akt can also be activated by heregulin, the effects of Grb2 inhibition on Akt were examined. Akt was inactivated following Grb2 downregulation in heregulin-stimulated breast cancer cells. We then examined the effects of Grb2 downregulation on Akt in ErbB2-overexpressing cells in the absence of heregulin. Similar to heregulin-stimulated cells, Grb2 inhibition also led to Akt inactivation in ErbB2-overexpressing breast cancer cells. Our results indicate that the activation of ErbB2 by heregulin or by its overexpression requires Grb2 to stimulate the Akt pathway to propagate mitogenic signals.

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Acknowledgements

We thank Alka Mehta for her excellent technical assistance and Doris Siwak for her critical reading of the manuscript. This work was supported in part by The University of Texas M.D. Anderson Breast Cancer Research Program (to AM Tari), and a postdoctoral fellowship from The Korea Science and Engineering Foundation and from The University of Texas M.D. Anderson Cancer Center Breast Cancer Research Program/US Army Breast Cancer Research Training Grant Program, Grant No. DAMD 17-99-1-9264 (to S-J Lim).

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Authors and Affiliations

  1. Department of Bioimmunotherapy, Section of Immunobiology and Drug Carriers, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Soo-Jeong Lim, Gabriel Lopez-Berestein & Ana M Tari

  2. Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Mien-Chie Hung

  3. Lawrence Berkeley National Laboratories, University of California Berkeley, Berkeley, CA, USA

    Ruth Lupu

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Lim, SJ., Lopez-Berestein, G., Hung, MC. et al. Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells. Oncogene 19, 6271–6276 (2000). https://doi.org/10.1038/sj.onc.1204014

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