Mitotic deregulation by survivin in ErbB2-overexpressing breast cancer cells contributes to Taxol resistance.

Abstract

PURPOSE:

Taxol resistance remains a major obstacle to improve the benefit of breast cancer patients. Here, we studied whether overexpression of ErbB2 may lead to mitotic deregulation in breast cancer cells via up-regulation of survivin that confers Taxol resistance.

EXPERIMENTAL DESIGN:

ErbB2-overexpressing and ErbB2-low-expressing breast cancer cell lines were used to compare their mitotic exit rate, survivin expression level, and apoptosis level in response to Taxol. Survivin was then down-regulated by antisense oligonucleotides to evaluate its contribution to mitotic exit and Taxol resistance in ErbB2-overexpressing breast cancer cells. At last, specific PI3K/Akt and Src inhibitors were used to investigate the involvement of these two pathways in ErbB2-mediated survivin up-regulation and Taxol resistance.

RESULTS:

We found that ErbB2-overexpressing cells expressed higher levels of survivin in multiple breast cancer cell lines and patient samples. ErbB2-overexpressing cells exited M phase faster than ErbB2-low-expressing cells, which correlated with the increased resistance to Taxol-induced apoptosis. Down-regulation of survivin by antisense oligonucleotide delayed mitotic exit of ErbB2-overexpressing cells and also sensitized ErbB2-overexpressing cells to Taxol-induced apoptosis. Moreover, ErbB2 up-regulated survivin at translational level and PI3K/Akt and Src activation are involved. In addition, combination treatment of Taxol with PI3K/Akt and Src inhibitor led to increased apoptosis in ErbB2-overexpressing breast cancer cells than single treatment.

CONCLUSIONS:

Survivin up-regulation by ErbB2 is a critical event in ErbB2-mediated faster mitotic exit and contributes to Taxol resistance.

• Authors: Jing Lu, Ming Tan, Wen-Chien Huang, Ping Li, Hua Guo, Ling-Ming Tseng, Xiao-hua Su, Wen-Tao Yang, Warapen Treekitkarnmongkol, Michael Andreeff, Fraser Symmans, Dihua Yu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 4 Pg. 1326-34 (Feb 15 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19228734 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Survivin
• Phosphatidylinositol 3-Kinases
• ERBB2 protein, human
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• Paclitaxel

Topics

• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Female
• Humans
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins (antagonists & inhibitors, physiology)
• Mitosis
• Paclitaxel (pharmacology)
• Phosphatidylinositol 3-Kinases (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Receptor, ErbB-2 (analysis)
• Survivin