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


METHODS
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.
Lu
Jing
J
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Tan
Ming
M
Huang
Wen-Chien
WC
Li
Ping
P
Guo
Hua
H
Tseng
Ling-Ming
LM
Su
Xiao-hua
XH
Yang
Wen-Tao
WT
Treekitkarnmongkol
Warapen
W
Andreeff
Michael
M
Symmans
Fraser
F
Yu
Dihua
D
D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008938:Mitosis; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000077022:Survivin
D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077022:Survivin; C107489:BIRC5 protein, human; C508053:ERBB2 protein, human