HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells

Christiane Knuefermann, Yang Lu, Bolin Liu, Weidong Jin, Ke Liang, Ling Wu, Mathias Schmidt, Gordon B. Mills, John Mendelsohn, Zhen Fan

Research output: Contribution to journalArticlepeer-review

357 Scopus citations

Abstract

Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. In this study, we delineated a pathway that involves HER2/PI-3K/Akt in mediating multidrug resistance in human breast cancer cells. We found that the cell lines that express both HER2 and HER3 appear to have a higher phosphorylation level of Akt (activated Akt). Transfection of HER2 in MCF7 breast cancer cells that express HER3 caused a phosphoinoside-3 kinase (PI-3K)-dependent activation of Akt, and was associated with an increased resistance of the cells to multiple chemotherapeutic agents (paclitaxel, doxorubicin, 5-fluorouracil, etoposide, and camptothecin). Selective inhibition of PI-3K or Akt activity with their respective dominant-negative expression vectors sensitized the cells to the induction of apoptosis by the chemotherapeutic agents. We further demonstrated that MCF7 cells expressing a constitutively active Akt, in which the phospholipid-interactive PH domain of Akt was replaced by a farnesylation sequence for constitutive membrane anchorage (ΔPH-Akt1-farn), showed a similar increased resistance to the chemotherapeutic agents. Our results suggest that activation of Akt1 by HER2/PI-3K plays an important role in conferring a broad-spectrum chemoresistance on breast cancer cells and that Akt may therefore be a novel molecular target for therapies that would improve the outcome of patients with breast cancer.

Original languageEnglish (US)
Pages (from-to)3205-3212
Number of pages8
JournalOncogene
Volume22
Issue number21
DOIs
StatePublished - May 22 2003
Externally publishedYes

Keywords

  • Akt
  • Breast cancer
  • Chemotherapy
  • HER2
  • PI-3K

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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