[837] A Tissue Microarray (TMA) Study of mTORC1 Pathway Expression in High Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Prostatic Adenocarcinoma (PCa)

S Evren, G Lockwood, N Fleshner, J Sweet. University Health Network, Toronto, ON, Canada

Background: The Mammalian Target of Rapamycin (mTOR) is a serine/threonine protein kinase and target of AKT. Activated mTOR (p-mTOR) associates with RAPTOR (mTORC1) or RICTOR (mTORC2). mTORC1 signaling promotes the activation of p70 ribosomal protein s6 kinase 1 (S6K1) and ribosomal protein s6 (RPS6), increasing ribosomal biogenesis and translation. This study presents the IHC expression of the mTORC1 pathway in prostate neoplasia. The expression of p-mTOR and RAPTOR and the effector molecules p-S6K1 and p-RPS6 were correlated in HGPIN and PCa using serial sections of TMAs.
Design: Four TMAs were constructed from radical prostatectomies as follows: HGPIN (35 cases), Gleason (GL) 6 (3+3) (35 cases), GL 7 (72 cases), HG PCa (GL 7, 8, 9) (37 cases). An additional TMA (28 cases) of benign prostatic tissue was constructed from benign prostates from cystoprostatectomies. Each case was represented by three 1mm cores. IHC was performed for p-mTOR, RAPTOR, p-S6K1, and p-S6RP on serial sections. Scanned TMAs were scored for the percentage of positive cells. Positive areas in each core were correlated for the 3 markers. Greater than 5% immunoreactivity in a core was considered positive. P values less than .05 were considered significant.
Results:

mTORC1 pathway expression in prostate neoplasia

	p-mTOR	RAPTOR	p-S6K1	P-RPS6
Nontumoral Prostate	17/28 (61%)	28/28 (100%)	16/22 (73%)	26/28 (93%)
HGPIN	29/35 (83%)	31/35 (89%)	35/35 (100%)	29/35 (83%)
GL6	26/35 (74%)	22/35 (63%)	23/35 (66%)	21/35 (60%)
GL7	50/72 (69%)	39/72(54%)	56/72 (78%)	53/37 (73%)
HG PCa	20/37 (54%)	25/37 (68%)	29/37 (78%)	29/37 (78%)

A Cochran-Armitage Trend analysis demonstrated decreasing p-mTOR activity progressing from PIN through GL6 and GL7 to HG PCa. Although, PCa and HGPIN showed a statistically significant difference in the expression of RAPTOR, p-S6K1 and p-S6RP, a trend amongst GL scores was not observed. There was considerable intratumoral IHC heterogeneity within an individual patient. However, a statistically significant correlation for p-mTOR, p-S6K1, and p-S6RP was observed in each representative core.
Conclusions: p-mTOR, RAPTOR, p-S6K1, and p-S6RP were highly expressed in HGPIN and may provide novel targets for its treatment. A decreasing trend in p-mTOR IHC was observed progressing from HGPIN to HG PCa. The extent of mTOR expression in an individual patient would determine the effective use of mTOR inhibitors as a potential therapeutic strategy.
Category: Genitourinary (including renal tumors)

Wednesday, March 24, 2010 9:30 AM

Poster Session V # 102, Wednesday Morning