Abstract 4906: A systems approach into studying the changes in genetic regulation during prostate cancer progression
Authors: Ylipää Antti , Waltering Kati , Zhang Wei , Visakorpi Tapio , Nykter Matti 
Published: June 2012

Prostate cancer (PC) is a complex disease that is currently the most common malignancy in males, and the second most frequent cause of cancer-related mortality in developed countries. Despite its high prevalence, the molecular mechanisms that induce PC progression are not well understood. The most common alterations affecting genetic regulation in PC are TMPRSS2:ERG gene fusions, 8q24 amplifications (including MYC-oncogene), and androgen receptor (AR) mutations and amplifications in castration-resistant (late stage) tumors. In normal prostatic tissue, local androgen metabolism maintains a balance between the proliferation and apoptotic cell death of prostatic epithelial cells. However in PC, androgen metabolism drives malignant transformation. The exact mechanisms which cause the imbalance in proliferation and apoptosis are not known, but likely include dysregulation of AR/MYC/ERG-regulated transcription factors (TFs) and/or microRNAs.

Using a systems biology approach, we jointly studied the accumulation of expression and copy number differences of TFs and microRNAs during PC progression. We first established a generic regulatory network consisting of transcription factors and microRNAs using three sets of sequence-based binding site predictions. First, TF binding sites were predicted by scanning the sequences upstream from gene transcription start sites for binding motifs from Transfac database, second, TF binding to microRNA promoters was predicted with ProbTF, and third, microRNA binding sites were obtained from Targetscan predictions. The inferred generic network was then adapted for studying PC by pruning it based on a set of publicly available gene expression, microRNA expression data. That is, we only considered those hypothetical regulatory connections that were supported by the data. By dividing these data into normal prostate tissue, primary PC's of different grade, and metastatic tumors, we were able to study the changes in regulation during different stages of the disease.

We uncovered putative regulatory motifs consisting of differentially expressed TFs and microRNAs. Another level of regulatory information was added by integrating copy number information to the regulatory motifs. We concentrated on the motifs that could be associated to AR-, ERG-, or MYC-signaling, due to their relevance in prostate cancer, or to molecules that are known to be regulated by these TFs. We found previously unknown microRNAs and TFs that may directly bound to the promoters of the TFs and therefore may have a critical effect to the malignancy of prostate cancers. The experimental validations of the most promising new candidate TF/microRNA regulatory connections are currently underway.

We demonstrated here an application of a systems biology based method to prostate cancer which was used to gain insights into the changes in genetic regulation during progression of the disease.

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 4906. doi:10.1158/1538-7445.AM2011-4906