Abstract 2398: Gene expression profiling of TgAPT121 mouse prostate reveals biological processes associated with early prostate carcinogenesis

Abstract

Abstract The TgAPT121 transgenic mice express a truncated SV40 T antigen (T121) in prostate epithelial cells and have been proposed as a model to study the early stages of prostate cancer (PCa) development. T121 expression inactivates the retinoblastoma family of proteins, causing epithelial hyperplasia, prostatic intraepithelial neoplasia (PIN) by 12-wk of age, and adenocarcinoma with microinvasion by 6-mo of age. Here we examined how the molecular features of the anterior prostate (AP) in this model relate to its histological presentation of PIN. TgAPT121 and non-transgenic control mice were raised to 12 wks, at which time the AP were removed and processed for histology (H&E) and RNA isolation (SV Total RNA Isolation kit; Promega). Transcripts were analyzed using the Affymetrix Mouse Gene 1.0 ST array. Data were preprocessed using Bioconductor packages, differentially expressed genes were identified by Significance Analysis of Microarray, and functional analysis was conducted using the MetaCore analysis suite (GeneGo, Inc.). More than 80% of the prostate epithelium developed PIN lesions and 4310 transcripts were significantly altered (5% FDR, fold-change ≥ 1.5; 3775 unique genes, 2443 up, 1332 down). Consistent with the PIN phenotype, functional analysis showed enrichment of GO terms and pathways related to cell cycle/proliferation, transcriptional activation through E2F1, c-Myc, NF-κB, AP-1, ETS1, and EGR1, DNA damage response, and apoptosis. Signaling through the androgen receptor (AR) and estrogen receptor alpha (ERα) have been shown to contribute to human PCa initiation and progression. Transcripts for components of the AR signaling pathway were increased in TgAPT121 mice, as were the transcriptional targets of AR and ERα. Cell adhesion and gap-junction components were downregulated, suggesting the loss of normal cell attachment and cell-cell communication controlling proliferation and differentiation. We next analyzed a published dataset of human PIN samples collected by laser-capture microdissection (GEO Database, GDS3289). Of the 4247 differentially expressed transcripts (5% FDR; 3868 unique genes, 2016 up, 1852 down), 489 overlapped with the differentially regulated genes from TgAPT121 mice (328 up, 161 down). Functional analysis of this subset of genes showed enrichment of pathways involved in cell cycle progression, apoptosis, DNA damage repair, as well as the disruption of gap junctions. This demonstrates that the early prostatic lesions in TgAPT121 mice share several essential molecular features with human PIN. Future research is needed to determine how these early features contribute to, and are altered along with, the progression of PCa in these mice. Supported by NIH Award CA101113 (JCF), NCI Cancer Prevention Interdisciplinary Education Program (YL), and Purdue Center for Cancer Research (JCF). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2398. doi:10.1158/1538-7445.AM2011-2398