The role of tumor suppressor PTEN in cancer development
dc.contributor.author | Kong, Dehe | |
dc.date.accessioned | 2012-04-04T15:10:45Z | |
dc.date.available | 2012-04-04T15:10:45Z | |
dc.date.issued | 2000 | |
dc.identifier.uri | http://hdl.handle.net/10713/1246 | |
dc.description | University of Maryland, Baltimore. Pathology. Ph.D. 2000 | en_US |
dc.description.abstract | The recently discovered candidate tumor suppressor gene located at chromosome 10q23.3, designated PTEN or MMAC1, was previously found to be mutated in a small percentage of several types of cancer. A high rate of loss of heterozygosity (LOH) has been reported at chromosome 10q23--26 in endometrial tumors. We performed mutational analysis of PTEN gene in genomic DNA samples from endometrial, gastric, colorectal, and pancreatic cancers. Results revealed that PTEN was mutated in 21 (55%) of 38 endometrial carcinomas: 14/18 (78%) of microsatellite instability-positive (MI+) and 7/20 (35%) of MI- cases. Eighteen (86%) of 21 tumors with mutations are predicted to produce truncated protein products. Two different mutations were present in each of five cases, while loss of heterozygosity (LOH) was observed in additional 8 tumors possessing only one mutation. No mutations were found in 9 pancreatic or 24 colorectal cancers, even in six colorectal cancers that were 10q-LOH-positive. Only one of 14 gastric cancers had a mutation. Six (27%) of 22 tumors with mutation had either insertions or deletions involving a poly(A6) tract in exon 8, suggesting a possible mutational hot spot in this gene. These results suggest that PTEN is an important tumor suppressor gene for endometrial cancers, particularly with those that are microsatellite instability positive (MI+). PTEN may also constitute a coding region target of microsatellite instability. Tumor suppressor PTEN is a dual-specificity phosphatase that is mutated in multiple advanced, metastatic human cancers. In order to discover potential mechanisms underlying suppression of cancer cell invasiveness and metastasis by PTEN, endogenously PTEN-mutant tumor cell lines were transfected with wild-type PTEN cDNA, invasiveness was analyzed using a modified invasion chamber assay, and several candidate targets of PTEN were evaluated. Exogenous wild-type PTEN reduced tyrosine phosphorylation of catenins, phosphatidylinositol 3-kinase (PI3-K) and focal adhesion kinase (FAK), and simultaneously inhibited the invasiveness of PTEN-mutant tumor cells. Wild-type PTEN also diminished both tyrosine and serine/threonine phosphorylation in c-Src and suppressed its kinase activity. These results suggest that c-Src is an important functional target for the phosphatase activity of PTEN which may be related to suppression of cancer cell invasiveness and metastasis by PTEN. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Biology, Molecular | en_US |
dc.subject | Health Sciences, Pathology | en_US |
dc.subject | Health Sciences, Oncology | en_US |
dc.subject | PTEN | en_US |
dc.subject.mesh | Carcinogenesis | en_US |
dc.subject.mesh | Genes, Tumor Suppressor | en_US |
dc.subject.mesh | Loss of Heterozygosity--genetics | en_US |
dc.title | The role of tumor suppressor PTEN in cancer development | en_US |
dc.type | dissertation | en_US |
dc.contributor.advisor | Meltzer, Stephen J. | |
dc.identifier.ispublished | Yes |