TMPRSS2:ERG (T/E) gene fusions are present in approximately 50% of all prostate cancer (PCa) cases. The expression of fusion mRNAs from distinct T/E variants is associated with clinicopathological parameters, while the underlying molecular processes remain unclear. We characterized the molecular mechanisms and functional implications caused by doxycycline (Dox)-inducible overexpression of the frequent T/E III and VI fusion variants in LNCaP cells. Induction of T/E expression resulted in increased cellular migratory and invasive potential, and reduced proliferation and accumulation in G1 phase. T/E overexpressing cells showed epithelial-to-mesenchymal transition (EMT), as demonstrated by upregulation of TGF-β and WNT pathway genes, mesenchymal markers, and increased phosphorylation of the p38 MAPK. Augmented secretion of TGF-β1 and –β2, and T/E-mediated regulation of ALK1, a member of the TGF-β receptor family, was detected. ALK1 inhibition in T/E overexpressing cells blocked p38 phosphorylation and reduced the expression of the TGF-β target genes VIM, MMP1, CDH2, and SNAI2. We found a T/E variant VI-specific induction of miR-503 associated with reduced expression of SMAD7 and CDH1. Overexpression of miR-503 led to increased levels of VIM and MMP1. Our findings indicate that TGF-β signaling is a major determinant of EMT in T/E overexpressing LNCaP cells. We provide evidence that T/E VI-specific transcriptional modulation by miR-503 accounts for differences in the activation of EMT pathway genes, promoting the aggressive phenotype of tumors expressing T/E variant VI. We suggest that ALK1-mediated TGF-β signaling is a novel oncogenic mechanism in T/E positive PCa.
In the past decade, multi-national and multi-center efforts were launched to sequence prostate cancer genomes, transcriptomes, and epigenomes with the aim of discovering the molecular underpinnings of tumorigenesis, cancer progression, and therapy resistance. Multiple biological markers and pathways have been discovered to be tumor drivers, and a molecular classification of prostate cancer is emerging. Here, we highlight crucial findings of these genome-sequencing projects in localized and advanced disease. We recapitulate the utility and limitations of current clinical practices to diagnosis, prognosis, and therapy, and we provide examples of insights generated by the molecular profiling of tumors. Novel treatment concepts based on these molecular alterations are currently being addressed in clinical trials and will lead to an enhanced implementation of precision medicine strategies.
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