Analysis of RAS as a tumor suppressor

Abstract

The RAS GTPases are among the best-understood oncogenes that promote human cancer. Many have argued that non-mutated, wild-type, RAS also functions as a tumor suppressor. The arguments for RAS tumor suppressor activity often involve data that are claimed to be inconsistent with known principles of RAS biology. RAS tumor suppressor activity is invoked to explain these observations. Here, we consider an alternative hypothesis: these data are actually consistent with RAS biology. We investigate by using our previously developed mathematical model of RAS regulation. We find that three of five arguments for RAS having tumor suppressor activity are based upon data that the model demonstrates are actually consistent with known RAS biology. We also find that the other two types of data interpreted to indicate a tumor suppressor effect can be explained by our model with the additional assumption that RAS protein expression does not vary proportionally with gene dosage. Measurements of RAS protein expression as a function of gene dosage could help resolve whether or not RAS has tumor suppressor activity. Overall, we conclude that the evidence for RAS having tumor suppressor activity is much less strong that it has appeared.