Abstract B12: The androgen receptor is a critical coactivator of Elk1 in prostate cancer cells
Authors: Suneethi Sivakumaran, Mesfin Gonit, Mugdha Patki, Robert Trumbly, Manohar Ratnam
Journal: Cancer Research (2011)

Abstract The androgen receptor (AR) not only plays an essential role in the physiology of the normal prostate but is also essential for the growth of most prostate tumors. The physiological actions of AR are primarily through its role as a transcription factor. AR mediates androgen-stimulated growth in the early stages of prostate cancer. AR also supports the growth of androgen ablation resistant advanced tumors that are either hypersensitized to androgen or that can grow in the complete absence of androgen through overexpression of AR, post-translational modifications of AR or AR mutations. The current paradigm for adjuvant therapy in prostate cancer is total and ubiquitous attenuation of AR signaling which has many undesirable side effects. Therefore it is desirable to develop functionally selective interventions by first identifying aspects of AR signaling that are only required by the cancer cells. In the classical mechanism of gene activation by AR the receptor, in response to hormone binding, localizes to the nucleus and binds as a homodimer to androgen response elements (AREs) to activate target genes. However, this laboratory has recently demonstrated that in prostate cancer cells in which AR is localized in the nucleus independent of hormone, the AR apo-protein can support growth without binding to ARE and likely by tethered associations with a distinct set of growth genes. In the present study, we used ChlP-chip and AR interactome data together with promoter activation assays to screen for DNA binding transcription factors that may serve to tether AR to target genes and are critical for AR dependent growth. Several candidate proteins were identified and further studies focused on Elk1. Elk1 belongs to the large Ets family of transcription factors and several signaling pathways impinge on this protein to regulate early growth response genes. Elk1 however is genetically and functionally redundant in normal tissues. Nevertheless, in our studies Elk1 was essential for the androgen or androgen receptor (AR)-dependent growth of cell line models of hormone-dependent early stage (LNCaP, VCaP) prostate cancer as well as advanced prostate cancer models, including both the AR overexpressing C4-2 cells and the non-overexpressing C81 cells. Elk1 supported a gene set strongly enriched for cell division functions in an androgen-dependent (in hormone-dependent cells) or AR-dependent manner. Using several approaches including promoter and gene activation assays, co-immunoprecipitation assays, mammalian two-hybrid assays and chromatin immunoprecipitation we established that AR associates with Elk1 as a coactivator. Elk1 could therefore serve as a functionally selective target for intervention in both early and advanced prostate cancer without a need for total attenuation of AR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B12.