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Immunohistochemical examination of the mTORC1 pathway in high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinomas (PCa): A tissue microarray study (TMA)
Author(s) -
Evren Sevan,
Dermen Arthur,
Lockwood Gina,
Fleshner Neil,
Sweet Joan
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21178
Subject(s) - pi3k/akt/mtor pathway , p70 s6 kinase 1 , mtorc1 , tissue microarray , cancer research , immunohistochemistry , ribosomal protein s6 , prostate cancer , biology , prostate , cancer , pathology , medicine , signal transduction , microbiology and biotechnology , genetics
BACKGROUND The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and a key regulator of protein synthesis and growth and is upregulated in many cancers. mTOR is activated by AKT phosphorylation (p‐mTOR). p‐mTOR associates with regulatory‐associated protein of TOR (RAPTOR), forming the mTORC1 complex. mTORC1 promotes the activation of p70 ribosomal protein s6 kinase 1 (p70 S6K1 ) and ribosomal protein s6 (RPS6). Upregulation of this pathway can lead to an aberrant increase in cell growth and metabolism characteristic of malignant transformation. METHODS This study presents the immunohistochemical (IHC) expression of the mTORC1 pathway in prostate neoplasia. The expression of p‐mTOR and RAPTOR and p‐p70 S6K1 and p‐RPS6 were examined in HGPIN and PCa using tissue microarrays (TMA). Since each case in our TMAs was represented by three tissue cores, we quantified the IHC intratumoral heterogeneity of mTOR expression. This extensive analysis is the first detailed assessment documenting the IHC heterogeneity of mTOR expression in HGPIN and prostate cancer and represents the first IHC description of the mTORC1 pathway in HGPIN and PCa. RESULTS A Cochran‐Armitage analysis demonstrated decreasing p‐mTOR activity progressing from PIN through GL6 and GL7 to HG PCa. There was considerable intratumoral IHC heterogeneity within an individual patient. However, a statistically significant correlation was observed between p‐mTOR, p‐p70 S6K1 , and p‐RPS6 in each representative core. CONCLUSION mTOR inhibitors may be an effective treatment for HGPIN and PCa. The extent of mTOR expression in an individual patient would determine the effective use of mTOR inhibitors as a potential therapeutic strategy. Prostate 70: 1429–1436, 2010. © 2010 Wiley‐Liss, Inc.