We and others have demonstrated that the loss of p27 expression in human tumors of the colon, prostate, breast, etc. correlates with poor prognosis. However, there is no understanding of why this is so. In a project to address this issue, we make use of the Rb+/- p27-/- mouse. Simply put, Rb+/- mice develop a pituitary adenocarcinoma following loss of the wild-type allele of Rb and a long latency period. Placing this mutation on a p27-deficient background, we demonstrated that this will accelerate the development of the tumor, presumably by decreasing latency, and that the tumor is much more aggressive. Thus, we have recapitulated the prognostic significance of p27 deficiency in a mouse model of pituitary tumorigenesis.
The goal now is to understand why. Is p27 deficiency altering the proliferation of these cells? Does it alter the negative regulatory input into these cells? One intriguing model is that the loss of p27 is preventing oncogenically primed cells (those that have lost Rb) from undergoing apoptosis induced by negative growth-regulatory signals. Indeed, this may represent a new modality by which cell cycle regulators can participate in tumor development. Work is continuing on the mouse model and cells obtained from embryonic mice, examining their growth and transformation properties.
