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

作者：Knuefermann C; Lu Y; Liu BL; Jin WD; Liang K; Wu L; Schmidt M; Mills GB; Mendelsohn J; Fan Z^*

来源：Oncogene, 2003, 22(21): 3205-3212.

DOI：10.1038/sj.onc.1206394

• HER2
• PI-3K
• Akt
• chemotherapy
• breast cancer

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 (DeltaPH-Akt1-farn), showed a similar increased resistance to the chemotherapeutic agents. Our results suggest that activation of AM 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.

• 出版日期2003-5-22