PTEN activation sensitizes breast cancer to PI3-kinase inhibitor through the β-catenin signaling pathway

Ren,Yu; Zhou,Xuan; Qi,Yanbin; Li,Guolan; Mei,Mei; Yao,Zhi

doi:10.3892/or.2012.1856

PTEN activation sensitizes breast cancer to PI3-kinase inhibitor through the β-catenin signaling pathway

Authors:
- Yu Ren
- Xuan Zhou
- Yanbin Qi
- Guolan Li
- Mei Mei
- Zhi Yao
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Affiliations: Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070, P.R. China, The First Department of Head and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China, Key Laboratory of Immuno Microenviroment and Disease of the Educational Ministry, Department of Immunology, Tianjin Medical University, Tianjin 300070, P.R. China
Published online on: June 12, 2012 https://doi.org/10.3892/or.2012.1856
Pages: 943-948

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Abstract

Combination therapy is considered a promising therapeutic modality in enhancing treatment efficacy. The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is almost universally dysregulated in breast cancer, with specific occurrence of PTEN mutations; thus, it has become an attractive target for cancer treatment. However, the use of single targeted therapeutics against the PI3K/AKT pathway has demonstrated only modest clinical benefits. In this study, recombinant adenovirus-mediated gene transfer of PTEN (AD-PTEN) combined with treatment with LY294002 was utilized to evaluate the effects of suppression of breast cancer cell proliferation. Herein, we show that AD-PTEN significantly enhanced the sensitization of breast cancer cells to LY294002. The 50% inhibitory concentration (IC50) values of LY294002 were significantly decreased to a greater extent in cells transfected with combination therapy. In addition, treatment of AD-PTEN-transfected cells with LY294002 resulted in significantly reduced cell viability and invasion ability compared to single LY294002 treatment. Using western blotting, we found that combination treatment resulted in lower levels of phosphorylated AKTSer473 and GSK-3βSer9 than single treatment with LY294002. Furthermore, we showed a significant decrease in nuclear β-catenin, Fra-1, Tcf-4 and c-Myc by combination treatment. Our results indicate that AD-PTEN sensitization of breast cancer to LY294002 is achieved by increased GSK-3β activity, thus resulting in inhibition of the β-catenin signaling pathway.

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