PURPOSE: Alterations of the androgen receptor (AR)-mediated signaling through numerous mechanisms are increasingly recognized in prostate cancer (CaP) progression. We hypothesized that the assessment of well-defined AR transcriptional targets (e.g., PSA/HK3 mRNA) in CaP tissues will provide in vivo readout of AR dysfunctions. Moreover, quantitative expression features of PSA/HK3 mRNA in prostate tumor cells may serve as a prognostic indicator of disease progression. EXPERIMENTAL DESIGN: Paired benign and malignant epithelial cells (242 specimens) were obtained from laser capture microdissection of frozen OCT-embedded tissue sections prepared from radical prostatectomy specimens of 121 patients. Quantitative expression of PSA/HK3 mRNA in the matched malignant and benign cells was analyzed by real-time reverse transcription-PCR. RESULTS: CaP cells express significantly lower PSA/HK3 mRNA levels than matched benign cells (P = 0.0133). Moreover, low PSA/HK3 mRNA expression in malignant cells was associated with increased risk of biochemical recurrence (P = 0.0217), as well as with time to recurrence (P = 0.0371), in patients with intermediate preoperative serum prostate-specific antigen levels (2-10 ng/mL). The expression of androgen-dependent genes in clinical samples correlates with each other in patients with higher expression of PSA/HK3 mRNA but not in patients with lower expression of PSA/HK3 mRNA reflecting AR pathway dysfunction. CONCLUSIONS: Our study has unraveled a novel prognostic utility of quantitative measurements of PSA/HK3 mRNA reflecting AR transcriptional activity in CaP cells, which is independent of serum prostate-specific antigen. It also has potential in stratifying subsets of patients exhibiting progressive disease associated with dampened AR transcriptional functions who may be targeted by tailored therapeutic strategies.
PURPOSE: Alterations of the androgen receptor (AR)-mediated signaling through numerous mechanisms are increasingly recognized in prostate cancer (CaP) progression. We hypothesized that the assessment of well-defined AR transcriptional targets (e.g., PSA/HK3 mRNA) in CaP tissues will provide in vivo readout of AR dysfunctions. Moreover, quantitative expression features of PSA/HK3 mRNA in prostate tumor cells may serve as a prognostic indicator of disease progression. EXPERIMENTAL DESIGN: Paired benign and malignant epithelial cells (242 specimens) were obtained from laser capture microdissection of frozen OCT-embedded tissue sections prepared from radical prostatectomy specimens of 121 patients. Quantitative expression of PSA/HK3 mRNA in the matched malignant and benign cells was analyzed by real-time reverse transcription-PCR. RESULTS: CaP cells express significantly lower PSA/HK3 mRNA levels than matched benign cells (P = 0.0133). Moreover, low PSA/HK3 mRNA expression in malignant cells was associated with increased risk of biochemical recurrence (P = 0.0217), as well as with time to recurrence (P = 0.0371), in patients with intermediate preoperative serum prostate-specific antigen levels (2-10 ng/mL). The expression of androgen-dependent genes in clinical samples correlates with each other in patients with higher expression of PSA/HK3 mRNA but not in patients with lower expression of PSA/HK3 mRNA reflecting AR pathway dysfunction. CONCLUSIONS: Our study has unraveled a novel prognostic utility of quantitative measurements of PSA/HK3 mRNA reflecting AR transcriptional activity in CaP cells, which is independent of serum prostate-specific antigen. It also has potential in stratifying subsets of patients exhibiting progressive disease associated with dampened AR transcriptional functions who may be targeted by tailored therapeutic strategies.
Authors: Russell Z Szmulewitz; Elizabeth Chung; Hikmat Al-Ahmadie; Silver Daniel; Masha Kocherginsky; Aria Razmaria; Gregory P Zagaja; Charles B Brendler; Walter M Stadler; Suzanne D Conzen Journal: Prostate Date: 2011-05-11 Impact factor: 4.104
Authors: K Mwamukonda; Y Chen; L Ravindranath; B Furusato; Y Hu; J Sterbis; D Osborn; I Rosner; I A Sesterhenn; D G McLeod; S Srivastava; G Petrovics Journal: Prostate Cancer Prostatic Dis Date: 2009-07-14 Impact factor: 5.554
Authors: Rute B Marques; Natasja F Dits; Sigrun Erkens-Schulze; Wilfred F J van Ijcken; Wytske M van Weerden; Guido Jenster Journal: PLoS One Date: 2011-08-04 Impact factor: 3.240
Authors: Hua Li; Ahmed A Mohamed; Shashwat Sharad; Elizabeth Umeda; Yingjie Song; Denise Young; Gyorgy Petrovics; David G McLeod; Isabell A Sesterhenn; Taduru Sreenath; Albert Dobi; Shiv Srivastava Journal: Oncotarget Date: 2015-06-20