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

Oncogene volume 22, pages 3205–3212 (2003)Cite this article

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.

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Abbreviations

ΔPH-Akt1-farn:

Flag-tagged farnesylation Akt1 lacking the PH domain

PI:

phosphatidylinositol

PI(3,4,5) P3:

PI 3,4,5-triphosphate

PI-3K:

phosphoinoside-3 kinase

FBS:

fetal bovine serum

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Acknowledgements

We are grateful to Michael Worley of the Department of Scientific Publications for editorial assistance with the manuscript. This work was supported in part by the US Army Department of Defense Medical Research Grant DAMD 17-00-1-0461, a grant from The Breast Cancer Research Foundation (New York), the NCI RO1 Grant CA82716, and Cancer Center core Grant CA16672.

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Author notes

  1. Mathias Schmidt

    Present address: Department of RPR/P3 Oncology Research, ALTANA Pharma AG, D-78467, Konstanz, Germany

Authors and Affiliations

  1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Christiane Knuefermann, Yang Lu, Bolin Liu, Weidong Jin, Ke Liang, Ling Wu, Mathias Schmidt, John Mendelsohn & Zhen Fan

  2. Department of Molecular Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Gordon B Mills & Zhen Fan

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  1. Christiane Knuefermann
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Correspondence to Zhen Fan.

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Knuefermann, C., Lu, Y., Liu, B. et al. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22, 3205–3212 (2003). https://doi.org/10.1038/sj.onc.1206394

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