Abstract
Abstract Introduction: Initially prostate cancer is driven by the male hormone androgen through the androgen receptor (AR). However, in some cases androgen receptor is functionally altered at late stages of tumorigenesis. Early knowledge of androgen receptor dysfunctions may assist in patient stratification for emerging therapeutic strategies. Although AR function can be altered by numerous mechanisms, the net effect of these changes is reflected in defective transcription factor functions of the AR. To develop readouts for AR function in prostate cancer we have evaluated the expression of a functionally relevant panel of AR-regulated genes in a prostate cancer cell culture model and in whole-mounted prostate tumor tissues. Methods: In the VCaP cell culture model of prostate cancer that endogenously express, AR, TMPRSS2-ERG fusion (ERG), KLK3 (PSA), NKX3.1, PMEPA1, ODC1 and AMD1 genes we have evaluated the dose and time kinetics of these AR regulated genes in response to androgen (R1881) treatment at protein and mRNA levels. Radical prostatectomy specimens representing favorable or poor prognostic cases were selected for the study. Each prostate was fixed, sectioned and immunohistochemical (IHC) staining on adjacent four-micron sections of the whole-mounted blocks were performed by using mouse monoclonal anti-AR, anti-ERG antibody (clone 9FY), rabbit polyclonal anti-PSA and anti-NKX3.1 antibodies. IHC intensities were scored and the final score was determined after multiplying the intensity score and percentage of positively stained area in the respective lesions. Results: Towards defining the expression levels of AR regulated genes in prostate cancer cells we have evaluated and confirmed the androgen dose and time kinetic response of endogenously expressed KLK3(PSA), PMEPA1, NKX3.1, ODC1, AMD1 and TMPRSS2-ERG (ERG) genes in VCaP cell culture model. Assessment of AR dysfunction by the immunohistochemical evaluation of AR regulated genes in whole-mounted prostate cancer specimens showed reduced expression of AR regulated genes in a sub-set of prostate cancer cases with notable inter- and intratumoral heterogeneity. Conclusions: Androgen regulation of examined genes was confirmed in VCaP prostate cancer cell culture model. Assessment of AR, ERG, NKX3.1 and PSA protein levels by IHC indicated reduced expression of AR-regulated genes in a subset of the cases. The analysis revealed inter- and intratumoral heterogeneity, as well as, challenges in the quantitative assessment of IHC. The observed readouts of AR dysfunction may provide a new tool for improved prognostic accuracy and patient stratification at early stages of prostate cancer treatment. Citation Format: Albert Dobi, Denise Young, Wei Huang, Lakshmi Ravindranth, Shashwat Sharad, Hua Li, Gyorgy Petrovics, David G. McLeod, Isabell Sesterhenn, Shiv Srivastava. Evaluation of androgen receptor function index (ARFI) in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1206. doi:10.1158/1538-7445.AM2013-1206
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