Abstract 1144: Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene

Abstract

Abstract Metastasis-associated protein 1 (MTA1) plays role in prostate cancer progression and metastasis. We have previously reported on the MTA1-targeted chemopreventive and therapeutic efficacy of pterostilbene (Pter) in the prostate-specific Pten heterozygous (Pten+/f; Pb-Cre+) and Pten null (Ptenf/f; Pb-Cre+) mice. To investigate the exact role of MTA1 in prostate cancer tumorigenesis and its early stages, we developed appropriate mouse models, namely prostate-specific MTA1-knocked in (MTA1-tg) and MTA1-tg on the background of prostate-specific Pten heterozygosity (MTA+/+, Pten+/f; Pb-Cre+). In the current project, we asked three major questions: 1) whether prostate MTA1 overexpression in the context of Pten loss promotes an earlier onset, greater total incidence and accelerated PIN or tumor growth rate; 2) what MTA1-associated molecules are involved in prostate cancer progression; and 3) whether Pter supplemented diet can provide beneficial effects. Identified from our ChIP-Seq data MTA1-associated molecules included CyclinD1, Notch2, and two neuroendocrine markers, namely CHGA and SYP. Using two prostate cancer cell lines, DU145 and PC3M and their corresponding MTA1 knockdown (shMTA1) clones, we validated the direct link between MTA1 and these markers on mRNA and protein levels. Further, we generated 28 prostate-specific MTA1+/+; Pten+/f; Pb-Cre+ mice and randomized them into two major groups: 1) mice on control diet (Ctrl-Diet) and 2) mice on Pter-Diet. After 5 months of feeding with corresponding diets (AIN-76A phytoestrogen free diets supplemented or not with Pter at 100 mg/kg/diet), mice were sacrificed and prostate tissues were isolated for histological, immunochemical and molecular analysis. Results demonstrated the contribution of MTA1 in more aggressive histological phenotype (Ki67, PCNA, p27, SMA, CK8), increased levels of oncogenic MTA1-guided molecules (CyclinD1, Notch2, CHGA, SYP, AR) and the potential for Pter in prostate cancer chemoprevention. Citation Format: Rutu Hemani, Ninad Inamdar, Avinash Kumar, Virginia Donovan, Anait S. Levenson. Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1144.