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  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).
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: firstname.lastname@example.org