PTEN IS ESSENTIAL FOR EMBRYONIC-DEVELOPMENT AND TUMOR SUPPRESSION

The PTEN gene encodes a dual-specificity phosphatase mutated in a vari ety of human cancers. PTEN germline mutations are found in three relat ed human autosomal dominant disorders, Cowden disease (CD), Lhermitte- Duclos disease (LDD) and Bannayan-Zonana syndrome (BZS), characterized by tumour susceptibility and developmental defects. To examine the ro le of PTEN in ontogenesis and tumour suppression, we disrupted mouse P TEN by homologous recombination. Pten inactivation resulted in early e mbryonic lethality. Pten(-/-) ES cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ec todermal and mesodermal derivatives. Pten(+/-) mice and chimaeric mice derived from Pten(+/-) ES cells showed hyperplastic-dysplastic change s in the prostate, skin and colon, which are characteristic of to, LDD and BZS. They also spontaneously developed germ cell, gonadostromal, thyroid and colon tumours. In addition, Pten inactivation enhanced the ability of ES cells to generate tumours in nude and syngeneic mice, d ue to increased anchorage-independent growth and aberrant differentiat ion. These results support the notion that PTEN haploinsufficiency pla ys a causal role in Co, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development.