Our findings: (i) further substantiate the mechanism of PTEN downregulation by PRL2 in vivo, (ii) demonstrate the potential of PRL2 inhibition for PTEN augmentation therapy in cancers that develop with WT PTEN expression and P53 mutations, and (iii) establish the efficacy of small-molecule inhibition of PRLs in an in vivo mouse tumor model for the first time. Here, PTEN is linked to cancer.