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

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 (DeltaPH-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.

• Authors: Christiane Knuefermann, Yang Lu, Bolin Liu, Weidong Jin, Ke Liang, Ling Wu, Mathias Schmidt, Gordon B Mills, John Mendelsohn, Zhen Fan
• Journal: Oncogene (Oncogene) Vol. 22 Issue 21 Pg. 3205-12 (May 22 2003) ISSN: 0950-9232 [Print] England
• PMID: 12761490 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Proto-Oncogene Proteins
• Receptor, ErbB-2
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Adenocarcinoma (drug therapy, enzymology, metabolism)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, enzymology, metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Enzyme Activation
• Female
• Humans
• Mutation
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt
• Receptor, ErbB-2 (metabolism)
• Signal Transduction
• Tumor Cells, Cultured