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1.  Aurora Kinase-A Inactivates DNA Damage Induced Apoptosis and Spindle Assembly Checkpoint Response Functions of p73 
Cancer cell  2012;21(2):196-211.
Elevated Aurora kinase-A expression is correlated with abrogation of DNA damage induced apoptotic response and mitotic spindle assembly checkpoint (SAC) override in human tumor cells. We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin. Aurora-A phosphorylated p73 also facilitates inactivation of SAC through dissociation of the MAD2-CDC20 complex in cells undergoing mitosis. Cells expressing phosphor-mimetic mutant (S235D) of p73 manifest altered growth properties, resistance to cisplatin induced apoptosis, as well as premature dissociation of the MAD2-CDC20 complex, and accelerated mitotic exit with SAC override in the presence of spindle damage. Elevated cytoplasmic p73 in Aurora-A overexpressing primary human tumors corroborates the experimental findings.
PMCID: PMC3760020  PMID: 22340593
2.  14-3-3ζ Cooperates with ErbB2 to Promote Progression of Ductal Carcinoma in Situ to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal Transition 
Cancer cell  2009;16(3):195-207.
ErbB2, a metastasis-promoting oncoprotein, is overexpressed in ~25% of invasive/metastatic breast cancers, but in 50–60% of non-invasive ductal carcinomas in situ (DCIS). It has been puzzling how a subset of ErbB2-overexpressing DCIS develops into invasive breast cancer (IBC). We found that co-overexpression of 14-3-3ζ in ErbB2-overexpressing DCIS conferred a higher risk of progression to IBC. ErbB2 and 14-3-3ζ overexpression, respectively, increased cell migration and decreased cell adhesion, two prerequisites of tumor cell invasion. 14-3-3ζ overexpression reduced cell adhesion by activating the TGFβ/Smads pathway that led to ZFHX1B/SIP-1 upregulation, E-cadherin loss, and epithelial-mesenchymal transition (EMT). Importantly, patients whose breast tumors overexpressed both ErbB2 and 14-3-3ζ had higher rates of metastatic recurrence and death than those whose tumors overexpressed only one.
PMCID: PMC2754239  PMID: 19732720
3.  High expression of ErbB2 contributes to cholangiocarcinoma cell invasion and proliferation through AKT/p70S6K 
AIM: To compare the impact of ErbB2 on cell invasion and proliferation in cholangiocarcinoma (CCA) cell lines.
METHODS: Level of endogenous ErbB2 expression in three CCA cell lines, namely HuCCA-1, KKU-100 and KKU-M213, was determined by real-time reverse-transcriptase polymerase chain reaction. Two ErbB2 inhibitory methods, a small molecule ErbB2 kinase inhibitor (AG825) and siRNA, were used to disrupt ErbB2 function in the cell lines. CCA cell invasion, motility and proliferation under ErbB2-disrupted conditions were detected using Transwell and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. In addition, ErbB2 downstream effectors were investigated by Western blotting analysis.
RESULTS: Suppression of ErbB2 activity, using a specific kinase inhibitor (AG825), reduced invasion, motility and proliferation of all three CCA cell lines. The ability of this drug to inhibit neoplastic properties (invasion, motility and proliferation) increased concomitantly with the level of ErbB2 expression. Similarly, knockdown of ErbB2 level by siRNA inhibited cell invasion and proliferation of KKU-M213, a high-ErbB2-expressing cell, better than those of the lower-ErbB2-expressing cells, HuCCA-1 and KKU-100. Thus, both inhibitory methods indicated that there is more ErbB2-dependency for malignancy of the high-ErbB2-expressing cell, KKU-M213, than for that of low-ErbB2-expressing ones. In addition, interrupting ErbB2 activity decreased phosphorylation of AKT and p70S6K, but not extracellular signal-regulated kinase 1/2, in the high-ErbB2-expressing CCA cell line.
CONCLUSION: Our data indicated that high ErbB2 expression enhances CCA invasion, motility and proliferation via the AKT/p70S6K pathway, which suggests the possibility of targeting these molecules for CCA therapy.
PMCID: PMC2928458  PMID: 20731018
AKT; Cholangiocarcinoma; ErbB2; Invasion; p70S6K; Cell proliferation
4.  Mitotic deregulation by survivin in ErbB2 overexpressing breast cancer cells contributes to Taxol resistance 
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 upregulation of survivin that confers Taxol resistance.
Experimental Design
ErbB2 over-expressing 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 downregulated by antisense oligonucleotides to evaluate its contribution to mitotic exit and Taxol resistance in ErbB2 over-expressing 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 upregulation and Taxol resistance.
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 over-expressing cells to Taxol-induced apoptosis. Moreover, ErbB2 upregulated survivin at translational level and both 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.
Survivin upregulation by ErbB2 is a critical event in ErbB2-mediated faster mitotic exit and contributes to Taxol resistance.
PMCID: PMC2663973  PMID: 19228734
breast cancer; ErbB2; survivin; mitotic deregulation; Taxol resistance

Results 1-4 (4)