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dc.contributor.authorKong, Dehe
dc.date.accessioned2012-04-04T15:10:45Z
dc.date.available2012-04-04T15:10:45Z
dc.date.issued2000
dc.identifier.urihttp://hdl.handle.net/10713/1246
dc.descriptionUniversity of Maryland, Baltimore. Pathology. Ph.D. 2000en_US
dc.description.abstractThe 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.isoen_USen_US
dc.subjectBiology, Molecularen_US
dc.subjectHealth Sciences, Pathologyen_US
dc.subjectHealth Sciences, Oncologyen_US
dc.subjectPTENen_US
dc.subject.meshCarcinogenesisen_US
dc.subject.meshGenes, Tumor Suppressoren_US
dc.subject.meshLoss of Heterozygosity--geneticsen_US
dc.titleThe role of tumor suppressor PTEN in cancer developmenten_US
dc.typedissertationen_US
dc.contributor.advisorMeltzer, Stephen J.
dc.identifier.ispublishedYes
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