Abstract 3200: A Novel Functional Role of ARF in Prostate Cancer

Abstract A Novel Functional Role of ARF in Prostate Cancer Zhenbang Chen,1,2,6 Arkaitz Carracedo,1,2 Hui-Kuan Lin,2 Jason A. Koutcher,3 Nille Behrendt,2 Ainara Egia,1,2 Andrea Alimonti1,2, Brett S. Carver,4 William Gerald,2 Julie Teruya-Feldstein,2 Massimo Loda,5 Pier Paolo Pandolfi 1,2* 1Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, New Research Building, 330 Brookline Avenue, Boston, MA 02115, USA. 2Department of Pathology, 3Departments of Medicine, Radiology and Medical Physics, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA. 4Human Oncology and Pathologenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. 5Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. 6Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 D. B. Todd Jr. Blvd., Nashville, TN 37208, USA Abstract PTEN and p53 are the two most frequently mutated and/or deleted genes in human cancers including prostate cancer, and their causal and synergistic cooperation remains elusive. Acute Pten inactivation induces a striking cellular senescence response both in mouse prostates and in primary mouse embryonic fibroblasts (MEFs) by activation of p19ARF-p53 pathway. Inactivation of Trp53 alone in mouse prostates fails to generate a tumor phenotype whereas complete inactivation of Pten in the prostate results in non-lethal invasive prostate cancer with long latency. Notably, concomitant inactivation of Trp53 and Pten in the prostate completely overcomes Pten-loss induced cellular senescence and invariably leads to a lethal cancer phenotype by 7 months of age. On the basis of the function coupling relationship between p19ARF and p53 proteins, we investigated the roles of p19ARF in prostate cancer. Surprisingly, we found that unlike Trp53, co-targeted inactivation of p19ARF and Pten in the prostate does not accelerate-but rather partially inhibits- the prostate cancer phenotype of Pten-deficient mice. Moreover, striking senescence features and a further reduction in the number of pre-neoplastic glands are observed in p19ARF-Pten compound mutants. Importantly, in both prostate epithelium and MEFs, induction of Trp53 protein abundance upon Pten loss is not affected by p19ARF deficiency. Surprisingly, p19ARF-deficiency significantly suppresses prostate cancer progression of Pten-Trp53 conditional double-mutant mice. In agreement with these findings, we find that in human prostate cancers, loss of PTEN was not associated with loss of p14ARF (human analog of mouse p19ARF). Collectively, our results reveal novel p53-uncoupled consequences for p19ARF loss leading to antitumor functions in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3200.