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.
PURPOSE:Taxol resistance remains a major obstacle to improve the benefit of breast cancerpatients. 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: Wenle Xia; John Bisi; Jay Strum; Leihua Liu; Kevin Carrick; Katherine M Graham; Amanda L Treece; Mary Ann Hardwicke; Michael Dush; Qiaoyin Liao; Ron E Westlund; Sumin Zhao; Sarah Bacus; Neil L Spector Journal: Cancer Res Date: 2006-02-01 Impact factor: 12.701
Authors: B M Ryan; G E Konecny; S Kahlert; H-J Wang; M Untch; G Meng; M D Pegram; K C Podratz; J Crown; D J Slamon; M J Duffy Journal: Ann Oncol Date: 2006-01-10 Impact factor: 32.976
Authors: Miguel Martín; Alvaro Rodríguez-Lescure; Amparo Ruiz; Emilio Alba; Lourdes Calvo; Manuel Ruiz-Borrego; Blanca Munárriz; César A Rodríguez; Carmen Crespo; Enrique de Alava; José Antonio López García-Asenjo; María Dolores Guitián; Sergio Almenar; Jesús Fernando González-Palacios; Francisco Vera; José Palacios; Manuel Ramos; Jose Manuel Gracia Marco; Ana Lluch; Isabel Alvarez; Miguel Angel Seguí; José Ignacio Mayordomo; Antonio Antón; José Manuel Baena; Arrate Plazaola; Alfonso Modolell; Amadeu Pelegrí; Jose Ramón Mel; Enrique Aranda; Encarna Adrover; José Valero Alvarez; José Luis García Puche; Pedro Sánchez-Rovira; Sonia Gonzalez; José Manuel López-Vega Journal: J Natl Cancer Inst Date: 2008-05-27 Impact factor: 13.506
Authors: Hao Liu; Christina Tekle; Yih-Wen Chen; Alexandr Kristian; Yuhua Zhao; Ming Zhou; Zixing Liu; Yan Ding; Bin Wang; Gunhild Mari Mælandsmo; Jahn Marthin Nesland; Oystein Fodstad; Ming Tan Journal: Mol Cancer Ther Date: 2011-04-25 Impact factor: 6.261
Authors: Nima Sharifi; Jun Qi; Susan Bane; Shubhada Sharma; Rui Li; Robert Robey; William D Figg; William L Farrar; David G I Kingston Journal: Mol Pharm Date: 2010-10-07 Impact factor: 4.939
Authors: Neeraj Kapur; Hina Mir; Guru P Sonpavde; Sanjay Jain; Sejong Bae; James W Lillard; Shailesh Singh Journal: Cancer Lett Date: 2019-04-08 Impact factor: 8.679
Authors: Ming Zhou; Yuhua Zhao; Yan Ding; Hao Liu; Zixing Liu; Oystein Fodstad; Adam I Riker; Sushama Kamarajugadda; Jianrong Lu; Laurie B Owen; Susan P Ledoux; Ming Tan Journal: Mol Cancer Date: 2010-02-09 Impact factor: 27.401