Abstract A55: ETS1 transcriptional activity promotes the castrate-resistant phenotype in prostate cancer.

Abstract

Abstract Androgen deprivation therapy (ADT) is the treatment of choice for advanced prostate cancer. ADT targets the transcriptional activity of the androgen receptor (AR) to inhibit prostate cancer tumor growth. Unfortunately, the success of this treatment is not sustained as tumors circumvent the effects of ADT by restoring AR transcriptional function to become castrate resistant. Despite recent improvements in the treatment of castrate resistant prostate cancer (CRPC), therapies remain palliative. Castrate resistance accounts for practically all prostate cancer mortalities, therefore preventing its occurrence by keeping tumors static, i.e., castrate sensitive, would significantly impact patient survival. Aberrant ETS1 (v-ets erythroblastosis virus E26 oncogene 1) activity is associated with poor prognosis in several tumor types through the transcriptional regulation of genes associated with aggressive cancer phenotypes. Our studies indicate that inhibition of ETS1 can restore sensitivity to ADT in castrate resistant cells and stall the invasive processes that promote its deadly effects. In human prostate cancer tissue ETS1 expression is increased in tumors Gleason 7 and above. In vitro, ETS1 expression and nuclear phosphorylation correlated with both aggression and the castrate resistant phenotype in the LNCaP model of prostate cancer progression. Targeted AR activity altered ETS1 expression levels and loss of ETS1 expression restored sensitivity to AR antagonist treatment in castrate resistant cells. AKT activity is increased in CRPC. Elevated AKT activity was demonstrated to increase ETS1 levels specifically in castrate resistant cells and exogenous ETS1 expression was sufficient to restore the invasive potential decreased by AKT inhibition. MMP1 (matrix metalloproteinase 1) is an ETS1 transcriptional target. Increased expression of MMP1 reflects the malignant phenotype and more aggressive tumor characteristics. ELISA assays show that MMP1 levels are increased in castrate resistant compared to castrate sensitive cells and are further increased by exogenous ETS1 expression. Luciferase reporter assays show that ETS1 significantly enhances MMP1 promoter activation in castrate resistant compared to castrate sensitive cells when exogenously expressed at comparable levels. In mouse xenograft models, increased ETS1 expression in castrate sensitive LNCaP cells promotes tumor growth to levels observed for castrate resistant cells. Significantly, exogenous ETS1 expression in castrate sensitive cells promotes tumor growth in androgen deprived (castrated) mice. Restoration of androgen receptor (AR) transcriptional activity is believed to be critical for progression to the castrate resistant phenotype. The mechanism by which AR activity is restored in CRPC remains unclear but increased co-recruitment of AR co-regulatory factors is critical. In combination these data suggest a role for ETS1 transcriptional function in promoting the restoration of AR transcriptional activity in castrate resistant cells. Citation Format: Ashley Marie Smith, Victoria Jane Findlay, Savannah Bandurraga, Emily Kistner-Griffin, Laura Spruill, Angen Liu, Ali Golshayan, David Paul Turner. ETS1 transcriptional activity promotes the castrate-resistant phenotype in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A55.