PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms.

We show in this study that PTEN regulates p53 protein levels and transcriptional activity through both phosphatase-dependent and -independent mechanisms. The onset of tumor development in p53(+/-);Pten(+/-) mice is similar to p53(-/-) animals, and p53 protein levels are dramatically reduced in Pten(-/-) cells and tissues. Reintroducing wild-type or phosphatase-dead PTEN mutants leads to a significant increase in p53 stability. PTEN also physically associates with endogenous p53. Finally, PTEN regulates the transcriptional activity of p53 by modulating its DNA binding activity. This study provides a novel mechanism by which the loss of PTEN can functionally control "two" hits in the course of tumor development by concurrently modulating p53 activity.

Genetic background controls tumor development in PTEN-deficient mice.

PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. Germ line mutations of PTEN have been detected in three rare autosomal-dominant disorders. However, identical mutations in the PTEN gene may lead to different symptoms that have traditionally been described as different disorders, such as Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndromes. This lack of genotype-phenotype correlation prompted us to directly test the possible effects of genetic background or modifier genes on PTEN-controlled tumorigenesis using genetically engineered mouse models. In this study, we generated two animal models in which either exon 5 (Pten(Delta5)) or promoter to exon 3 (Pten(-)) of the murine Pten gene were deleted and compared phenotypes associated with individual mutations on two genetic backgrounds. We found that the onset and spectrum of tumor formation depend significantly on the genetic background but less on the type of mutation generated. Our results suggest that PTEN plays a critical role in cancer development, and genetic background may influence the onset, the spectrum, and the progression of tumorigenesis caused by Pten mutation.

Giant cell glioblastoma and pleomorphic xanthoastrocytoma show different immunohistochemical profiles for neuronal antigens and p53 but share reactivity for class III beta-tubulin.

CONTEXT: Giant cell glioblastoma multiforme (GCGBM) and pleomorphic xanthoastrocytoma (PXA) are clinically, radiographically, and histologically distinct tumors of the central nervous system. However, they share features of gross circumscription, reticulin deposition, lymphocytic infiltrates, and prominent populations of tumor giant cells. Neuronal antigens have been detected in the neoplastic cells of PXAs, but to our knowledge have not been studied previously in GCGBMs. While TP53 is mutated in most GCGBMs, a feature usually paralleled by strong immunostaining of the protein, the expression pattern of PXAs has not been extensively studied. OBJECTIVES: To compare the immunoprofiles of GCGBM and PXA with regard to neuronal antigens and p53 and to evaluate the potential diagnostic utility of such a panel. DESIGN: Archival paraffin sections of 9 GCGBMs and 9 PXAs were immunostained for class III beta-tubulin, neuronal nuclear antigen, neurofilament protein, synaptophysin, glial fibrillary acidic protein, and p53. RESULTS: Giant cell glioblastomas were strongly immunoreactive for class III beta-tubulin and glial fibrillary acidic protein, but showed only rare staining for the other neuronal polypeptides. In contrast, PXAs usually showed at least focal staining of individual tumor cells for most of the neuronal antigens tested. Tubulin was strongly positive in tumor giant cells and in smaller neoplastic cells of both tumor types. Double-immunolabeling revealed distinct populations of tumor cells that expressed either glial fibrillary acidic protein or tubulin and dual-labeling of individual cells in GCGBM and PXA. Strong p53 staining was observed in many tumor cells in 5 of 8 GCGBMs tested, while staining for this antigen was negative or focally positive in 6 of 8 PXAs examined. CONCLUSIONS: Giant cell glioblastoma multiforme and PXA show distinct patterns of immunoreactivity for neuronal antigens and p53 that may be useful diagnostically in difficult cases or in limited samples. These results provide further evidence of neuronal antigen expression by PXA.

Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland.

PTEN tumor suppressor is frequently mutated in human cancers, including breast cancers. Female patients with inherited PTEN mutations suffer from virginal hypertrophy of the breast with high risk of malignant transformation. However, the exact mechanisms of PTEN in controlling mammary gland development and tumorigenesis are unclear. In this study, we generated mice with a mammary-specific deletion of the Pten gene. Mutant mammary tissue displayed precocious lobulo-alveolar development, excessive ductal branching, delayed involution and severely reduced apoptosis. Pten null mammary epithelial cells were disregulated and hyperproliferative. Mutant females developed mammary tumors early in life. Similar phenotypes were observed in Pten-null mammary epithelia that had been transplanted into wild-type stroma, suggesting that PTEN plays an essential and cell-autonomous role in controlling the proliferation, differentiation and apoptosis of mammary epithelial cells.