Abstract B005: The oncogenic transcription factor ERG has distinct roles and signaling regulation in different prostate cancer cell types

Abstract

Abstract Background: ERG is the most common oncogene in prostate cancer, as it is aberrantly expressed in about 50% of cases due to the TMPRSS2/ERG gene rearrangement. ERG is not normally expressed in the adult prostate. The normal function of ERG is confined to hematopoietic stem cells and blood vessels. Aberrant expression of ERG in prostate epithelial cells is oncogenic when combined with mutations that activate the PI3K/AKT signaling pathway. The RAS/MAPK pathway can also regulate ERG function through direct phosphorylation of ERG by ERK. The function of these regulatory events and how they can be exploited to develop therapy for ERG-positive prostate cancer remains unclear. Results: ERG expression in prostate basal epithelial cells drives epithelial to mesenchymal transition and stemness properties. This function requires ERG phosphorylation via a positive feedback loop with the TLR4 signaling pathway, and can be repressed by a TLR4 inhibitor. Activation of the PI3K/AKT pathway rearranges the ERG cistrome and alters ERG function, where ERG now promotes luminal epithelial differentiation. In the presence of activated AKT, new ERG targets include genes involved in vascular development and ERG phosphorylation is regulated through a positive feedback loop with the VEGF signaling pathway. Conclusions: ERG function in basal and luminal prostate epithelial cells appear to mirror ERG functions in hematopoietic stem cells and blood vessels, respectively. These findings suggest strategies of combinatorial inhibition of ERG function in both cell types. Citation Format: Peter C. Hollenhorst, Saranya Rajendran, Travis J. Jerde. The oncogenic transcription factor ERG has distinct roles and signaling regulation in different prostate cancer cell types [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B005.