Mice lacking the p27Kip1 Cdk inhibitor, like mice lacking Rb, develop
pituitary tumors involving pars intermedia melanotrophs, yet p27(Kip1)
tumors are genetically distinct from Rb derived
tumors as they exhibit haploid insufficiency. We compared
tumors from mice with p27( Kip1) constitutive and tissue specific null mutations to
tumors arising in tissue specific Rb knockout mice with the aim of determining whether they are distinguished by quantitative or qualitative differences. The rate of p27Kip1 knockout
tumor development was strongly influenced by strain background due to polygenic strain modifiers in the C57BL/6J versus 129S4 strains but, unlike a prior report of Rb mutants, this impacted
tumor incidence but not the
tumor spectrum. p27Kip1
tumors were oligoclonal or polyclonal based on studies of X-chromosomal inactivation of Dock11. In contrast, Rb null tissue developed monoclonal
neoplasms even in the absence of a requirement for Rb mutant clonal selection. Rb null
tumors exhibited a higher proliferation rate and developed ischemic
necrosis associated with an aberrant vasculature. p27Kip1 null
tumors maintained normal vascular density, through a
tumor cell dependent mechanism, but were more often hemorrhagic. Gene expression profiles distinguished p27Kip1 from Rb null
tumors including significant differences in expression of Rb and E2F signature genes. Rb null
tumors expressed higher levels of
VEGF which, in other systems, is associated with dilated vessels, ineffective perfusion and tissue
hypoxia. Mouse models lacking p27Kip1 and Rb may help us better understand the pathophysiology of MEN syndromes,
retinoblastoma and other
cancers that disrupt these important cell cycle inhibitors.