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

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.

• Authors: Yu Ren, Xuan Zhou, Yanbin Qi, Guolan Li, Mei Mei, Zhi Yao
• Journal: Oncology reports (Oncol Rep) Vol. 28 Issue 3 Pg. 943-8 (Sep 2012) ISSN: 1791-2431 [Electronic] Greece
• PMID: 22710837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chromones
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Recombinant Proteins
• beta Catenin
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adenoviridae (genetics)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromones (pharmacology, therapeutic use)
• Enzyme Activation
• Female
• Genetic Therapy
• Humans
• Inhibitory Concentration 50
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Morpholines (pharmacology, therapeutic use)
• PTEN Phosphohydrolase (biosynthesis, genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Recombinant Proteins (biosynthesis, genetics)
• Signal Transduction
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• beta Catenin (metabolism)