1. ¹Division of Urology, Department of Surgery, University of Kentucky Medical Center, Lexington, Kentucky, USA
2. ²Department of Pathology and Laboratory Medicine, University of Kentucky Medical Center, Lexington, Kentucky, USA
3. ³Department of Molecular and Cellular Biochemistry, University of Kentucky Medical Center, Lexington, Kentucky, USA

Correspondence: N Kyprianou, Division of Urology, MS-283, University of Kentucky Medical Center, 800, Rose Street, Lexington, KY 40536, USA. E-mail: nkypr2@uky.edu

Received 12 February 2004; Revised 30 June 2004; Accepted 14 July 2004; Published online 12 October 2004.

Abstract

Early diagnosis of prostate cancer holds tremendous promise for the effective therapy and impact on survival of prostate cancer patients. High-grade prostatic intraepithelial neoplasia (HGPIN) is generally accepted as a lesion indicative of a late pathological event in the premalignant changes leading to full development of prostate cancer. This review seeks to identify specific molecular events that may be linked directly to the molecular transition from benign prostate epithelial cells to prostate carcinoma. HGPIN is pathologically detected in a limited group of men undergoing prostate cancer screening for an elevated serum prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE). Loss of apoptotic control provides a molecular basis for the contribution of specific defective steps in the pathway towards development and progression of prostate cancer. Comparative dissection of the apoptosis status and expression profile of key apoptotic regulators among foci of highly proliferative benign prostatic epithelium, PIN and prostate adenocarcinoma from adjacent areas of the same gland revealed a novel insight into the dysfunctional apoptosis events contributing to prostate carcinogenesis. The sequential and notable loss of the three critical signaling components of the apoptotic action of transforming growth factor- (TGF-), in the prostate, that is, the transmembrane receptor II (TRII), the key cell cycle inhibitor p27^Kip1, as well as the protagonist downstream effector of the TGF- signaling mechanism, Smad4, points to their potential value to 'faithfully' characterize HGPIN, as a premalignant prostate lesion. Recent evidence on the molecular changes in apoptosis regulators contributing to HGPIN and their role as molecular markers of disease onset, as well as candidates for therapeutic targeting/chemoprevention of prostate cancer in its early stages will be discussed.