PTEN activation sensitizes breast cancer to PI3-kinase inhibitor through             the β-catenin signaling pathway.
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.
Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070, PR China.
Yu
Y
Ren
Xuan
X
Zhou
Yanbin
Y
Qi
Guolan
G
Li
Mei
M
Mei
Zhi
Z
Yao
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology* / Q000627:therapeutic use; D004789:Enzyme Activation; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins; D051176:beta Catenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human