IJCEP Copyright © 2007-All rights reserved.
Int J Clin Exp Pathol 1(4):333-342;2008

Original Article
Morphoproteomic Confirmation of a Constitutively Activated mTOR Pathway in High
Grade Prostatic Intraepithelial Neoplasia and Prostate Cancer

Robert E. Brown, George Zotalis, Ping L. Zhang and Bihong Zhao

Department of Pathology and Laboratory Medicine, University of Texas Health Science Center - Medical School at Houston, Houston, TX and
Department of Laboratory Medicine, Geisinger Medical Center, Danville, PA

Received 13 Sept 2007; accepted and available online 1 January 2008

Abstract: Preclinical studies have implicated the mammalian target of rapamycin (mTOR) pathway in the cell cycle progression and growth of
prostate cancer cells. Downstream signaling from PI3'-K/Akt leads to phosphorylation (p) of mTOR at serine 2448 and to activation of its
substrate, p70S6Kinase (p70S6K), phosphorylated on threonine 389. This promotes translation and cell cycle progression. Morphoproteomic
analysis, that combines both the application of phosphospecific probes directed against putative sites of activation on protein analytes and
cellular compartmentalization [1] was carried out on tissue microarray (TMA) slides from 64 cases of primary, previously untreated
adenocarcinomas of the prostate. Gleason scores ranged from 6 to 10. High grade prostatic intraepithelial neoplasia (HGPIN), which
accompanied the invasive cancer in 20 cases, and 15 non-neoplastic controls from benign prostatic hypertrophy specimens in a separate TMA
were also included. Ninety-three percent (93%) of tumors exhibited moderate to strong cytoplasmic/plasmalemmal expression of p-mTOR and
eighty-five percent (85%) showed similar staining intensity for p-p70S6K. HGPIN demonstrated comparable and occasionally, stronger
expression levels for these protein analytes. Quantitative digital imaging revealed an overall increase in the mean expression levels in HGPIN,
reaching statistical significance for p-mTOR (Ser 2448) at p<0.05. Morphoproteomic analysis confirms the constitutive activation of the mTOR
pathway in prostate cancer and HGPIN, with relative overexpression of p-mTOR in HGPIN. These findings coincide with preclinical studies in
supporting a role for the mTOR pathway in the biology and development of prostate cancer through its putative precursor lesion, HGPIN and in
suggesting a potential therapeutic target. (IJCEP709008).

Key Words: mTOR pathway, prostate cancer, high grade PIN, morphoproteomics, tissue microarray

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Address all correspondence to: Robert E. Brown, M.D., Department of Pathology & Laboratory Medicine, University of Texas Health Science
Center-Houston Medical School, 6431 Fannin Street, MSB 2.286, Houston, TX 77030, USA; Tel: 713-500-5332;Fax: 713-500-0695; Email: