PTEN/MMAC1/TEP1: (hereafter PTEN) is a tumor suppressor gene (located at 10q23) that is frequently mutated or deleted in sporadic human
tumors. PTEN encodes a multifunctional
phosphatase, which negatively regulates cell growth, migration and survival via the
phosphatidylinositol 3'-kinase/AKT signalling pathway. Accordingly, Pten+/- mice develop various types of
tumors including
teratocarcinomas and
teratomas. We have investigated PTEN expression in 60 bioptic specimens of
germ cell tumors (32
seminomas, 22
embryonal carcinomas and six
teratomas) and 22 intratubular germ cell
neoplasias (ITGCN) adjacent to the
tumors for
PTEN protein and
mRNA expression. In total, 10 testicular biopsies were used as controls. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of
seminomas as well as from 86% of
embryonal carcinomas and virtually all
teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not an early event in
testicular tumor development. The loss of PTEN expression occurs mainly at the
RNA level as determined by in situ hybridization of cellular
mRNA (17/22) but also it may involve some kind of post-transcriptional mechanisms in the remaining 25% of cases. Analysis of microsatellites D10S551, D10S541 and D10S1765 in GCTs (n=22) showed LOH at the PTEN locus at 10q23 in at least 36% of GCTs (three
embryonal carcinoma, three
seminoma, two
teratoma); one
seminoma and one embryonal (9%)
carcinoma presented an inactivating mutation in the PTEN gene (2/22). Finally, we demonstrated that the
phosphatidylinositol 3'-kinase/AKT pathway, which is regulated by the
PTEN phosphatase, is crucial in regulating the proliferation of the NT2/D1 embryonal carcinoma cells, and that the
cyclin-dependent kinase inhibitor p27(kip1) is a key downstream target of this pathway.