PTEN level in tumor suppression: how much is too little?

The importance of PTEN (phosphatase and tensin homolog located on chromosome 10) in cancer has surpassed all predictions and expectations from the time it was discovered and has qualified this gene as one of the most commonly mutated and deleted tumor suppressors in human cancer. PTEN levels are frequently found downregulated in cancer, even in the absence of genetic loss or mutation. PTEN is heavily regulated by transcription factors, microRNAs, competitive endogenous RNAs (such as the PTEN pseudogene), and methylation, whereas the tumor suppressive activity of the PTEN protein can be altered at multiple levels through aberrant phosphorylation, ubiquitination, and acetylation. These regulatory cues are presumed to play a key role in tumorigenesis through the alteration of the appropriate levels, localization, and activity of PTEN. The identification of all these levels of PTEN regulation raises, in turn, a key corollary question: How low should PTEN level(s) or activity drop in order to confer cancer susceptibility at the organismal level? Our laboratory and others have approached this question through the genetic manipulation of Pten in the mouse. This work has highlighted the exquisite and tissue-specific sensitivity to subtle reductions in Pten levels toward tumor initiation and progression with important implications for cancer prevention and therapy.