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 journalArticle

    350 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

    Keywords

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

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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  • Cite this

    Knuefermann, C., Lu, Y., Liu, B., Jin, W., Liang, K., Wu, L., Schmidt, M., Mills, G. B., Mendelsohn, J., & 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