ETS1 transcriptional activity is increased in advanced prostate cancer and promotes the castrate-resistant phenotype

Abstract

Advanced disease accounts for the majority of prostate cancer-related deaths and androgen deprivation therapy (ADT) is the standard of care for these patients. Many patients undergoing ADT become resistant to its effects and progress to castrate-resistant prostate cancer (CRPC). Current therapies for CRPC patients are inadequate, with progression-free survival rates as low as 2 months. The molecular events that promote CRPC are poorly understood. ETS (v-ets erythroblastosis virus E26 oncogene) transcription factors are regulators of carcinogenesis. Protein levels of the archetypical ETS factor, ETS1, are increased in clinical and latent prostate cancer relative to benign prostatic hyperplasia and normal prostate to promote multiple cancer-associated processes, such as energy metabolism, matrix degradation, survival, angiogenesis, migration and invasion. Our studies have found that ETS1 expression is highest in high-grade prostate cancer (Gleason 7 and above). Increased ETS1 expression and transcriptional activity promotes an aggressive and castrate-resistant phenotype in immortalized prostate cancer cells. Elevated AKT (v-akt murine thymoma viral oncogene homolog) activity was demonstrated to increase ETS1 protein levels specifically in castrate-resistant cells and exogenous ETS1 expression was sufficient to rescue invasive potential decreased by inhibition of AKT activity. Significantly, targeted androgen receptor activity altered ETS1 expression, which in turn altered the castrate-resistant phenotype. These data suggest a role for oncogenic ETS1 transcriptional activity in promoting aggressive prostate cancer and the castrate-resistant phenotype.