HIGH CANCER SUSCEPTIBILITY AND EMBRYONIC LETHALITY ASSOCIATED WITH MUTATION OF THE PTEN TUMOR-SUPPRESSOR GENE IN MICE

Background: Germ-line and sporadic mutations in the tumor suppressor g ene PTEN (also known as MMAC or TEP1), which encodes a dual-specificit y phosphatase, cause a variety of cancers such as Cowden disease, glio blastoma, endometrial carcinoma and prostatic cancer. PTEN is widely e xpressed, and Cowden disease consistently affects various organ system s, suggesting that the PTEN protein must have an important, although a s yet poorly understood, function in cellular physiology. Results: Hom ozygous mutant mice lacking exons 3-5 of the PTEN gene (mPTEN(3-5)) ha d severely expanded and abnormally patterned cephalic and caudal regio ns at day 8.5 of gestation. Embryonic death occurred by day 9.5 and wa s associated with defective chorio-allantoic development. Heterozygous mPTEN3-5 mice had an increased incidence of tumors, especially T-cell lymphomas; gamma-irradiation reduced the time lapse of tumor formatio n. DNA analysis of these tumors revealed the deletion of the mPTEN gen e due to loss of heterozygosity of the wild-type allele. Tumors associ ated with loss of heterozygosity in mPTEN showed elevated phosphorylat ion of protein kinase B (PKB, also known as Akt kinase), thus providin g a functional connection between mPTEN and a murine proto-oncogene (c -Akt) involved in the development of lymphomas. Conclusions: The mPTEN gene is fundamental for embryonic development in mice, as mPTEN3-5 mu tant embryos died by day 9.5 of gestation, with patterning defects in cephalic and caudal regions and defective placentation. Heterozygous m ice developed lymphomas associated with loss of heterozygosity of the wildtype mPTEN allele, and tumor appearance was accelerated by gamma-i rradiation, These lymphomas had high levels of activated Akt/PKB, the protein product of a murine proto-oncogene with anti-apoptotic functio n, associated with thymic lymphomas. This suggests that tumors associa ted with mPTEN loss of heterozygosity may arise as a consequence of an acquired survival advantage. We provide direct evidence of the role o f mPTEN as a tumor suppressor gene in mice, and establish the mPTEN mu tant mouse as an experimental model for investigating the role of PTEN in cancer progression.