A critical role for p27^kip1 gene dosage in a mouse model of prostate carcinogenesis

In human prostate cancer, the frequent down-regulation of p27 ^kip1 protein expression is correlated with poor clinical outcome, yet p27^kip1 rarely undergoes mutational inactivation. Here, we investigate the consequences of reducing or eliminating p27^kip1 function for prostate carcinogenesis in the context of a mouse modeling lacking the Nkx3.1 homeobox gene and the Pten tumor suppressor. Unexpectedly, we find that triple mutant mice heterozygous for a p27^kip1 null allele (Nkx3.1^{+/- or -/-}; Pten^+/-; p27^+/-) display enhanced prostate carcinogenesis, whereas mice that are homozygous null for p27^kip1 (Nkx3.1^{+/- or -/-}; Pten^+/-; p27 ^-/-) show inhibition of cancer progression. Expression profiling reveals that Cyclin D1 is highly up-regulated in compound p27^kip1 heterozygotes, but is down-regulated in the compound p27^kip1 homozygous mutants. Using RNA interference in prostate cancer cell lines with distinct p27^kip1 gene doses, we show that prostate tumorigenicity depends on levels of p27^kip1 and that the consequences of p27 ^kip1 gene dosage can be attributed, in part, to altered levels of Cyclin D1. Our findings suggest that p27^kip1 possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression.