Susceptibility of p27 kip1 knockout mice to urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine may not simply be due to enhanced proliferation

Int J Cancer. 2008 Mar 15;122(6):1222-8. doi: 10.1002/ijc.23249.


Deregulated proliferation is one of the fundamental characteristics of carcinogenesis. p27 is one of the most well characterized negative cell cycle regulator. In our previous study, expression of p27 protein was found to be dramatically suppressed on stimulation of cell proliferation by calculi in the rodent urinary bladder, withdrawal of the insult resulting in re-expression of p27 and regression of urothelial hyperplastic lesions. In the present study, to evaluate how loss of function impacts on urinary bladder carcinogenesis, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), a bladder carcinogen was given to p27 knockout mice. Males and females with either null, hetero or wild-type p27 alleles were divided into 2 groups, one given drinking water containing 0.05% BBN for 10 weeks and the other receiving distilled water, then, killed at week 20. The experiment was repeated for confirmation of the outcome. In the second experiment, performed with a larger number of animals, the incidence of urinary bladder carcinomas was significantly higher in female p27-null mice than in their wild-type counterparts. p27 deficiency also resulted in their increase of relative weights of urinary bladders and section areas of carcinomas in BBN-treated mice. Interestingly, while BrdU labeling indices generally increased with progression of mucosal proliferative lesions, from normal epithelium, through hyperplasia to carcinoma, there was no significant variation with the p27 genotype, in tumors as well as normal urothelium. These findings suggest that p27 deficient mice have elevated susceptibility to BBN-induction of urinary bladder carcinogenesis through a mechanism which might be independent of acceleration of cell cycling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Body Weight / drug effects
  • Butylhydroxybutylnitrosamine / toxicity*
  • Carcinogens / toxicity*
  • Cell Proliferation / drug effects*
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / physiology*
  • DNA Primers
  • Female
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size / drug effects
  • Urinary Bladder Neoplasms / chemically induced*
  • Urinary Bladder Neoplasms / pathology


  • Carcinogens
  • DNA Primers
  • Cyclin-Dependent Kinase Inhibitor p27
  • Butylhydroxybutylnitrosamine