Abstract B06: Abi1 levels regulate prostate tumor progression in mice downstream from Pten inactivation

With over 200,000 new cases and nearly 30,000 deaths every year, prostate cancer remains one of the most critical healthcare issues in the United States. Prostate cancer is progressive, eventually leading to an aggressive and metastatic disease. Although indolent disease can be left untreated (watchful waiting or symptomatically treated), predicting which tumors will progress to the metastatic and lethal stage of the disease is problematic. More comprehensive knowledge of disease-progression mechanisms in prostate cancer treatment decisions would offer considerable saving to society in treatment costs and effort, and would likely improve patient quality of life by reducing the number of patients treated with radical therapies. Mouse models recapitulate well many stages of human pathology associated with prostate tumor progression. Tumor invasiveness involves dysregulation of actin cytoskeleton. Abi1 is the key component of actin polymerization regulatory WAVE complex. WAVE complex plays important role in a variety of cellular processes, including protrusion formation during cell migration and the formation of adherens junctions, indicating the critical importance of Abi1 for cell-to-cell adhesion and cell motility. ABI1 is implicated in variety of human cancers including initiation of prostate cancer (Oncogenesis. 2012; 1:e26) but its role in tumor progression is unknown. In a search for molecular mechanism of tumor progression here we modeled the effect of ABI1 inactivation in absence of PTEN gene, which is the most commonly mutated gene in human prostate cancer. Prostate specific inactivation of Pten and Abi1 genes in mice led to establishment of progression-specific prostate tumorigenesis models in mice. Preliminary data indicate that Abi1 controls tumor invasiveness resulting from Pten loss in a dose dependent manner. By modifying Abi1 and Pten gene dose using the double Abi1/Pten KO mouse, three models of prostate cancer progression were produced: Model 1, a model of invasive carcinoma (complete Pten and Abi1 loss, mice with the genotype: [Abi1(fl/fl); Pten(fl/fl); PbCre+]); Model 2, a model of changes consistent with high grade PIN with partial progression to invasive carcinoma (complete Pten loss, single copy of Abi1 present, mice with the genotype: [Abi1(wt/fl); Pten(fl/fl); PbCre+]); and, Model 3, a model of noninvasive prostate cancer with development of changes similar to low grade PIN (complete Abi1 loss, single copy of Pten present, mice with the genotype: [Abi1(fl/fl); Pten(wt/fl); PbCre+]). Histopathological changes observed in Abi1/Pten double KO are being compared to Pten KO alone to evaluate the influence of Abi1 on dynamics of tumor progression due to Pten loss. Analysis of Abi1/Pten double KO mice indicates that activation of PI-3 kinase activity is coincident with abnormal regulation of actin cytoskeleton. Examination of molecular and biochemical changes indicate that Pten inactivation alone resulted in up-regulation of Abi1 levels. Hence, Abi1 inactivation-mediated abrogation of oncogenic effects due to Pten loss in the double Abi1/Pten KO mouse is consistent with Abi19s tumor suppressor function. We propose that Abi1 levels control tumor progression by controlling level of actin dysregulation associated with tumor invasion. As Abi1/WAVE complex and Pten dysregulation are observed in human pathology it is hoped that the analysis of Abi1/Pten KO mouse model will lead to better understanding of tumor progression in human prostate cancer and to translation of the findings from bench to bedside. Citation Format: Anna Chorzalska, Xiaoling Xiong, Andrea Lunardi, Julie R. White, Janet A. Sawicki, Gennady Bratslavsky, Pier Paolo Pandolfi, Leszek Kotula. Abi1 levels regulate prostate tumor progression in mice downstream from Pten inactivation. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B06.