Abstract 5107: A novel MTA1 knock-in mouse model for the mechanistic and therapeutic studies of MTA1-driven prostate cancer
Authors: Kumar Avinash , Dhar Swati , Butt Nasir A. , Phadatare Pravin R. , Dholakia Kshiti , Vedula Jogarao , Donovan Virginia , Levenson Anait S. 
Published: August 2018

Metastasis-associated protein 1 is known to play role in prostate cancer progression and metastasis. Studies of MTA1-mediated prostate cancer tumorigenesis, progression and metastasis have been hampered by a lack of suitable experimental system. Here we describe a new conditional mouse model that shows strong MTA1 expression in the prostate. This model was generated through MTA1 transgene knocked into the mouse ROSA26 (R26) locus using CAG-LoxP-Stop-LoxP (LSL)-2HA-MTA1-T2A-GFP-pA construct (Applied StemCell,Inc, Menlo Park, CA). Briefly, after generation of a genetically modified founder mouse line Rosa26-3attP, resulted MTA1 transgene embryos were injected into foster mice to produce MTA1 founders, designated as R26-LSL-MTA1. To monitor tumor formation and development in live animals by using IVIS, we have crossbred R26-LSL-MTA1 with Pb-Cre+;Luc and generated transgenic lines that express MTA1 and Luc upon Cre-mediated removal of the LSL cassette, specifically in the prostate epithelium (Pb-Cre+;R26MTA1;R26Luc) (MTA1-tg). We confirmed prostate-specific expression of the MTA1 transgene on mRNA and protein levels. We evaluated prostate histology for differences in histology of control normal prostates (Pb-Cre-; MTA1-tg) and MTA1-tg mice at as early as 13-weeks of age. MTA1 overexpressing prostate showed signs of mPIN characterized by glandular structures composed of atypical proliferating luminal cells that fill out the lumen. We detected differences in cellular proliferation, as determined by increased PCNA and decreased p27 as well as Ki67 immunofluorescent staining in MTA1-tg prostate. Moreover, expression of several oncogenic MTA1-guided molecules was increased in the prostates of MTA1-tg mice. We have previously reported on the role of MTA1-mediated signaling in prostate tumor progression in the prostate-specific Pten heterozygous (Pb-Cre+; Pten+/f) and Pten null (Pb-Cre+; Ptenf/f ) mice. To determine the role of MTA1 overexpression in the context of PTEN loss, we generated MTA1-tg; Pten+/f and MTA1-tg; Ptenf/f mice to evaluate whether MTA1overexpression in the prostate promotes an earlier onset, greater total incidence, accelerated tumor growth rate and metastasis. We predict that MTA1 overexpression will cause higher activation of downstream pathways to promote cancer cell survival, which will result in increased incidence of invasive adenocarcinoma and probably lymph node metastasis. Mice will be sacrificed at different time points for prostate tissue and lymph nodes isolation and subsequent histopathological, immunochemical and molecular evaluation.

Citation Format: Avinash Kumar, Swati Dhar, Nasir A. Butt, Pravin R. Phadatare, Kshiti Dholakia, Jogarao Vedula, Virginia Donovan, Anait S. Levenson. A novel MTA1 knock-in mouse model for the mechanistic and therapeutic studies of MTA1-driven prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5107.