Pten and p27(KIP1) cooperate in prostate cancer tumor suppression in the mouse

The genetic bases underlying prostate tumorigenesis are poorly understood. Inactivation of the tumor-suppressor gene PTEN and lack of p27(KIP1) expres sion have been detected in most advanced prostate cancers(1,2). But mice de ficient for Cdkn1b (encoding p27(KIp1)) do not develop prostate cancer(3-5) . PTEN activity leads to the induction of p27(KIP1) expression, which in tu rn can negatively regulate the transition through the cell cycle(6). Thus, the inactivation of p27(KIP1)may epistatic to PTEN in the control of the ce ll cycle. Here we show that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transfor mation and incidence of tumors of various histological origins. Cell prolif eration, but not cell survival, is increased in Pten(+/-)/Cdkn1b(-/-)mice. Moreover, Pten(+/-)/Cdkn1b(-/-) mice develop prostate carcinoma at complete penetrance within three months from birth. These cancers recapitulate the natural history and pathological features of human prostate cancer. Our fin dings reveal the crucial relevance of the combined tumor-suppressive activi ty of Pten and p27(Kip1) through the control of cell-cycle progression.