Abstract 2014: Alternative splicing is a frequent event in mouse PTEN-deficient prostate cancer

Abstract

Abstract Castration-resistant prostate cancer (CRPC) remains an incurable disease and presents a major challenge for the development of novel treatment strategies. Alternative splicing occurs as a common natural phenomenon and promotes diversity, however, cancer-related alternative splicing events have been shown to contribute to disease progression and promote therapeutic escape. In prostate cancer, key genes required for normal biological function are frequently alternatively spliced resulting in altered phenotypes. Novel therapeutic strategies targeting the alternative splicing machinery are being developed and tested. Here, characterized the conditional PTEN-deficient mouse model of prostate cancer to determine its relevancy as preclinical tool for the development and efficacy determination of novel therapeutic strategies targeting aberrant alternative splicing. For this, we used the Affymetrix GeneChip mouse transcriptome assay to perform comparative analysis of the transcriptomes of normal prostate tissue and PTEN-deficient castration-naïve, castration-sensitive (4 weeks post-castration), and castration-resistant (10 weeks post-castration) prostate cancers. Clustering analysis revealed genes enriched with the functions involved in mRNA splicing and processing in mice with prostate tumors. Moreover, alternative splicing events were more prevalent in castration-sensitive tumors (>2.5-fold) compared to castration-naïve and castration resistant tumors. Exon skipping (cassette exon), was the most common splicing event observed in all conditions. Additionally, alternative splicing was observed in several genes frequently associated with human prostate cancer including CD44, AR, p53, Bcl2l1 and Klf6 among others. Collectively, our data shows that alternative mRNA splicing is a frequent event in mouse PTEN-deficient prostate cancer and supports a role for alternative splicing dysregulation and the pathogenesis of the disease. Furthermore, this mouse model may also provide a suitable platform to study current therapeutic approaches targeting alternative splicing. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Alternative splicing is a frequent event in mouse PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2014.