Abstract B7: ETS1 overexpression in prostate cancer cells

Abstract

Abstract The ETS1 transcription factor is overexpressed in human prostate cancers in comparison to nonmalignant prostate and exhibits nuclear, in addition to aberrant cytoplasmic localisation. A previous report has identified direct interaction between ETS1 and the androgen receptor (AR) in the prostate cancer cell line, LNCaP and we have demonstrated that this ligand-dependent interaction is mediated via the ETS (DNA binding) domain of ETS1 and the ligand-binding domain of the AR. In a cohort of 44 prostate cancer cases, mRNA for the full-length ETS1 isoform, p54ETS1 was detected in all prostate tumour and adjacent nonmalignant prostate tissues, while expression of the internally truncated p42ETS1 isoform was very low or undetectable. In protein lysates extracted from the same cases, p54ETS1 was detected in all samples, with expression of a lower molecular weight ETS1 corresponding in size to the dominant negative p27ETS1 isoform also observed. Increased expression of one or both of the ETS1 isoforms was identified in 38 (86%) cases, supporting the elevated expression of ETS1 in human prostate tumours. Both ETS1 and the AR upregulate expression of the prostatic tumour suppressor, NKX3.1 via sequences located in the 5′ promoter and 3′ untranslated region (3′UTR), respectively. Although unresponsive to androgens, the proximal ∼2kb of the NKX3.1 promoter, and in particular a 76bp sequence surrounding the ETS binding site (EBS) become androgen responsive following ETS1 overexpression. In addition, in LNCaP cells that stably overexpress p54ETS1, the biphasic proliferative responses to androgens, where low (≤10−10M) DHT concentrations stimulate proliferation and higher (>10−10M) DHT levels inhibit proliferation, were altered and DHT concentrations as low as 10−12M inhibited proliferation. The findings indicate that the increased expression of ETS1 commonly observed in human prostate tumours may modify the androgen responsiveness of the cancer cells, augmenting AR-mediated regulation of androgen target genes and potentially sensitising prostate cancer cells to the very low androgen levels in men treated with androgen ablation therapies. Citation Format: Jacqueline M. Bentel, Jennet Harvey, Marc A. Thomas, Jamie J. Rodgers, Ebony J. Rouse, Darren M. Preece, Siaw M. Chai, Michael R. Epis, Ronald J. Cohen, Peter J. Leedman, Kimberley Roehrig. ETS1 overexpression in prostate cancer cells [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 B7.