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 Mills, John Mendelsohn, Zhen Fan

Research output: Contribution to journalArticle

344 Citations (Scopus)

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

Fingerprint

Multiple Drug Resistance
Adenocarcinoma
Breast
Phosphotransferases
Breast Neoplasms
Prenylation
Camptothecin
Growth Factor Receptors
MCF-7 Cells
Etoposide
Paclitaxel
Fluorouracil
Doxorubicin
Transfection
Signal Transduction
Phospholipids
Phosphorylation
Apoptosis
Drug Therapy
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Knuefermann, C., Lu, Y., Liu, B., Jin, W., Liang, K., Wu, L., ... Fan, Z. (2003). HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene, 22(21), 3205-3212. https://doi.org/10.1038/sj.onc.1206394

HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. / Knuefermann, Christiane; Lu, Yang; Liu, Bolin; Jin, Weidong; Liang, Ke; Wu, Ling; Schmidt, Mathias; Mills, Gordon; Mendelsohn, John; Fan, Zhen.

In: Oncogene, Vol. 22, No. 21, 22.05.2003, p. 3205-3212.

Research output: Contribution to journalArticle

Knuefermann, C, Lu, Y, Liu, B, Jin, W, Liang, K, Wu, L, Schmidt, M, Mills, G, Mendelsohn, J & Fan, Z 2003, 'HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells', Oncogene, vol. 22, no. 21, pp. 3205-3212. https://doi.org/10.1038/sj.onc.1206394
Knuefermann, Christiane ; Lu, Yang ; Liu, Bolin ; Jin, Weidong ; Liang, Ke ; Wu, Ling ; Schmidt, Mathias ; Mills, Gordon ; Mendelsohn, John ; Fan, Zhen. / HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. In: Oncogene. 2003 ; Vol. 22, No. 21. pp. 3205-3212.
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