Dubovenko A1, Serebryiskaya T1, Nikolsky Y1, Nikolskaya T2, Perlina A1, JeBailey L3, Bureeva S1, Katta S4, Srivastava S4, Dobi A4, Khasanova T5.
1. Thomson Reuters, IP & Science, 5901 Priestly Dr., 200, Carlsbad, CA 92008, USA;
2. 29608 Via Rancheros, Fallbrook, CA 92028, USA;
3. Novartis Institute for Biomedical Research, 250 Massachusets Ave, Cambridge, MA, USA;
4. Center for Prostate Cancer Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA;
5. Rancho Biosciences, PO Box 7208, Rancho Santa Fe, CA, 92067, USA.
Despite a growing number of studies evaluating cancer of prostate (CaP) specific gene alterations, oncogenic activation of the ETS Related Gene (ERG) by gene fusions remains the most validated cancer gene alteration in CaP. Prevalent gene fusions have been described between the ERG gene and promoter upstream sequences of androgen-inducible genes, predominantly TMPRSS2 (transmembrane protease serine 2). Despite the extensive evaluations of ERG genomic rearrangements, fusion transcripts and the ERG oncoprotein, the prognostic value of ERG remains to be better understood. Using gene expression dataset from matched prostate tumor and normal epithelial cells from an 80 GeneChip experiment examining 40 tumors and their matching normal pairs in 40 patients with known ERG status, we conducted a cancer signaling-focused functional analysis of prostatic carcinoma representing moderate and aggressive cancers stratified by ERG expression.
In the present study of matched pairs of laser capture microdissected normal epithelial cells and well-to-moderately differentiated tumor epithelial cells with known ERG gene expression status from 20 patients with localized prostate cancer, we have discovered novel ERG associated biochemical networks.
Using causal network reconstruction methods, we have identified three major signaling pathways related to MAPK/PI3K cascade that may indeed contribute synergistically to the ERG dependent tumor development. Moreover, the key components of these pathways have potential as biomarkers and therapeutic target for ERG positive prostate tumors.
Prostate cancer; TMPRSS2-ERG fusion.; differentiation status