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

Soo Jeong Lim, Gabriel Lopez-Berestein, Mien Chie Hung, Ruth Lupu, Ana M. Tari

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 down-regulation 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-over-expressing breast cancer cells. Our results indicate that the activation of ErbB2 by heregulin or by its over-expression requires Grb2 to stimulate the Akt pathway to propagate mitogenic signals.

Original languageEnglish (US)
Pages (from-to)6271-6276
Number of pages6
JournalOncogene
Volume19
Issue number54
DOIs
StatePublished - Dec 14 2000
Externally publishedYes

Fingerprint

GRB2 Adaptor Protein
Neuregulin-1
Down-Regulation
Breast Neoplasms
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Intercellular Signaling Peptides and Proteins
Proteins
Cell Proliferation

Keywords

  • Akt
  • Breast cancer
  • ErbB2
  • Grb2
  • Heregulin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells. / Lim, Soo Jeong; Lopez-Berestein, Gabriel; Hung, Mien Chie; Lupu, Ruth; Tari, Ana M.

In: Oncogene, Vol. 19, No. 54, 14.12.2000, p. 6271-6276.

Research output: Contribution to journalArticle

Lim, Soo Jeong ; Lopez-Berestein, Gabriel ; Hung, Mien Chie ; Lupu, Ruth ; Tari, Ana M. / Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells. In: Oncogene. 2000 ; Vol. 19, No. 54. pp. 6271-6276.
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