The role of tumor suppressor PTEN in cancer development

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.