Immunohistochemical examination of the mTORC1 pathway in high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinomas (PCa): a tissue microarray study (TMA).
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.


CONCLUSIONS
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.
Evren
Sevan
S
Department of Laboratory Medicine, University Health Network, Toronto, ON, Canada.
Dermen
Arthur
A
Lockwood
Gina
G
Fleshner
Neil
N
Sweet
Joan
J
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D016009:Chi-Square Distribution; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010766:Phosphorylation; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D011506:Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases