Abstract The phosphatases of regenerating liver (PRL) phosphatases are frequently overexpressed in a wide variety of human cancers and are correlated with cancer progression, metastasis, and poor patient outcomes. Although PRLs appear to be linked to oncogenesis, it is not yet fully understood whether PRL overexpression is sufficient to drive spontaneous tumorigenesis in vivo or the mechanisms by which PRLs contribute to cancer. To address this gap, we developed a novel genetically modified mouse model that conditionally overexpresses PRL2 in the prostate epithelium, mimicking the onset of human cancers. Our findings indicate that transgenic overexpression of PRL2 leads to a multifocal low-grade prostatic intraepithelial neoplasia (LGPIN) phenotype, with a rare occurrence of malignancy in older mice. Furthermore, elevated PRL2 promotes significant acceleration and progression from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostatic adenocarcinoma mediated by PTEN heterozygosity, whereas PRL2 overexpression is dispensable for PTEN-loss-mediated transformation. The initiation and progression of prostate cancer following PRL2 overexpression correlate with decreased PTEN levels and upregulation of AKT/mTOR pathways. Taken together, these findings elucidate the pivotal role of proto-oncogenic PRL2 in promoting tumorigenesis through the downregulation of PTEN. Therefore, PRLs are compelling therapeutic targets for cancer drug discovery, and PRL2 inhibition may be a novel approach for cancer treatment through PTEN augmentation in both PTEN-deficient and wild-type backgrounds. Citation Format: Jingmei Yu, Frederick Nguele Meke, Yunpeng Bai, Meaghan Maureen Broman, Haoran Zhang, Abhinanda Kar, Zhong-Yin Zhang, . Mechanism of oncogenicity induced by overexpression of the PRL phosphatases abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5994.
Yu et al. (Fri,) studied this question.