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Function and Regulatory Mechanisms of the Candidate Tumor Suppressor Receptor Protein Tyrosine Phosphatase Gamma (PTPRG) in Breast Cancer Cells

2010; International Institute of Anticancer Research (IIAR) Conferences 1997. Athens, Greece. Abstracts; Volume: 30; Issue: 6 Linguagem: Inglês

1791-7530

Sherry T. Shu, Y. Sugimoto, Suling Liu, Hsiang-Lin Chang, Weiping Ye, Li‐Shu Wang, Yi‐Wen Huang, Pearlly S. Yan, Young C. Lin,

Cytokine Signaling Pathways and Interactions

Background: Protein phosphorylation is one of the essential steps in cell signaling, and aberrant phosphorylation is a common event in human cancer. The expression of receptor type protein tyrosine phosphatase gamma (PTPRG) in normal breast is found to be ~50-60% higher than that of breast tumor tissue. Overexpression of PTPRG inhibits anchorage-independent growth and proliferation of breast cancer cells. To understand the tumor suppression characteristics of PTPRG, we studied its tumor suppressive function in an athymic mouse model and evaluated factors that can potentially regulate its expression in breast cancer cells. Materials and Methods: To investigate the function of PTPRG in vivo, athymic nude mice were implanted with MCF-7 cells overexpressing PTPRG. For in vitro study, protein levels of cell cycle regulators, cell cycle re-entry, and the phosphorylation levels of extracellular signal-regulated protein kinases 1/2 (ERK1/2) were examined. In addition, methylation assays were conducted to investigate the epigenetic modification on the promoter of PTPRG. Results: Athymic nude mice bearing MCF-7 cells overexpressing PTPRG showed a reduction in tumor burden in comparison to animals implanted with MCF- 7 cells transfected with vector alone. When these two cell lines were studied in an in vitro system, elevated mRNA and protein levels of cell cycle regulators, p21 cip and p27 kip were detected in MCF-7 cells overexpressing PTPRG compared to cells transfected with vector alone. Similarly, overexpression of PTPRG also delayed the re-entry of breast cancer cells into the cell cycle after serum starvation, and reduced the phosphorylation levels ERK1/2 in MCF-7 cells. In addition, methylation assays in PTPRG promoter in breast cancer cell lines (including SK-Br-3) revealed an aberrant methylation pattern. When SK-Br-3 and MCF-7 cells were treated with deoxy-5-azacytidine (DAC) and trichostatin A (TSA), these compounds reactivated the expression of PTPRG, suggesting an epigenetic control on its expression. Conclusion: Our results indicated that PTPRG inhibited breast tumor formation in vivo; PTPRG may up-regulate p21 cip and p27 kip proteins