We propose that the PTRE-HPRT system presented in this study represents a valid model for initiation and progression of aberrant silencing in cancer because silenced PTRE-HPRT alleles display the hallmarks of tumor suppressor gene silencing (promoter region DNA methylation, histone hypoacetylation, loss of methyl-K4 H3, and gain of methyl-K9 H3). This evidence concerns the gene HPRT1 and cancer.