High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice

Abstract

The mPTEN gene is fundamental for embryonic development in mice, as mPTEN3-5 mutant embryos died by day 9.5 of gestation, with patterning defects in cephalic and caudal regions and defective placentation. Heterozygous mice developed lymphomas associated with loss of heterozygosity of the wild-type mPTEN allele, and tumor appearance was accelerated by gamma-irradiation. These lymphomas had high levels of activated Akt/PKB, the protein product of a murine proto-oncogene with anti-apoptotic function, associated with thymic lymphomas. This suggests that tumors associated with mPTEN loss of heterozygosity may arise as a consequence of an acquired survival advantage. We provide direct evidence of the role of mPTEN as a tumor suppressor gene in mice, and establish the mPTEN mutant mouse as an experimental model for investigating the role of PTEN in cancer progression.

Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo

“…Germ-line mutations of PTEN have also been suggested as the underlying genetic lesion in Cowden disease , an inherited autosomal syndrome characterized by increased incidence of breast and thyroid tumors; and in Bannaya-Zonana Syndrome, a disorder characterized by intestinal hamartomas and neurological abnormalities . In vivo studies in mouse models have demonstrated that heterozygous PTEN disruption causes hyperplastic-dysplastic changes in the prostate, skin and colon, similar to those observed in Cowden disease (Di Cristofano et al, 1998;Suzuki et al, 1998), providing additional evidence for the role of PTEN in tumor suppression.…”

Mouse models for colorectal cancer

“…Inactivation mutation in mice reveal a necessary function for Pten during embryogenesis, but a percentage of heterozygous mice also show colonic carcinomas (Di Cristofano et al, 1998;Suzuki et al, 1998).…”

Mouse models of prostate cancer

“…As an aside, prostatic hyperplasia (but not neoplasia) also has been observed after the targeted inactivation of various tumor suppressor genes including nkx3.1 (Bhatia-Gaur et al, 1999), p27kip1 (Cordon-Cardo et al, 1998), pten (Di Cristofano et al, 1998;Podsypanina et al, 1999;Suzuki et al, 1998), estrogen receptor beta (Krege et al, 1998), and mxi1 (Schreiber-Agus et al, 1998). Finally, since the techniques associated with the MPR model are challenging, this system has been exploited thus far primarily by its originators (Buttyan, 1997;Green et al, 1998).…”