1. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells.
- Author
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Knuefermann, Christiane, Lu, Yang, Liu, Bolin, Jin, Weidong, Liang, Ke, Wu, Ling, Schmidt, Mathias, Mills, Gordon B, Mendelsohn, John, and Fan, Zhen
- Subjects
HER2 gene ,DRUG resistance ,CANCER cells ,BREAST cancer - 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 (?PH-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.Oncogene (2003) 22, 3205-3212. doi:10.1038/sj.onc.1206394 [ABSTRACT FROM AUTHOR]
- Published
- 2003
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