The phosphatidylinositol 3' kinase-Akt-mammalian target of rapamycin pathway in smooth muscle tumors of the uterus: selected protein expression patterns and their clinicopathologic implications.

ABSTRACT

Preclinical analyses strongly implicate the phosphatidylinositol 3' kinase-Akt-mammalian target of the rapamycin (P13K-Akt-mTOR) signaling pathway in smooth muscle tumorigenesis and differentiation, indicating that this pathway may be a suitable molecular target for the development of anticancer chemotherapeutic agents. The purpose of this study is to define the frequency and patterns of expression of 3 proteins in this pathway (mTOR, Akt, and PI3-K) in smooth muscle tumors of the uterine corpus, and to establish whether the expression of any of these proteins has independent prognostic significance. The expression patterns of mTOR, pan-Akt, and PI3-K were evaluated by immunohistochemistry in 31 uterine leiomyosarcomas and 10 leiomyomata, and the results were correlated with clinicopathologic parameters. Cases were scored by multiplication of staining intensity (on a 0 to 3+scale) and the extent/distribution of immunoreactivity (on a 0 to 4+ scale) for potential scores that ranged from 0 to a maximum of 12. Cases with scores of 4+to 12+(moderate, 4+ to 8+; high, 9+ to 12+ immunoreactivity) were considered positive. Associated peritumoral normal myometrium was present in 27 cases. All 31 leiomyosarcomas were pan-Akt positive, with 80.6% of the positive cases displaying high scores, whereas all 10 leiomyomata and 27 normal myometria were entirely pan-Akt negative. High pan-Akt scores were associated with high tumor grade but not with advanced stage or outcome. Every tumoral and nontumoral sample that was evaluated showed immunoreactivity for mTOR. PI3-K was positive in 20 (64.5%) of the 31 leiomyosarcomas but in none of the leiomyomata. High scores of PI3-K were associated with late pathologic stage (P=0.0022). High PI3-K scores, high pan-Akt scores, and PI3-K positivity were not independently associated with reduced disease-specific survival on multivariate analysis. Our findings suggest that relative to the normal myometrium, there is indeed dysregulation of the P13K-Akt-mTOR pathway in uterine smooth muscle tumors and especially in uterine leiomyosarcomas. Pan-Akt, mTOR, and PI3-K expression lacked independent prognostic significance in this pilot study, but additional and larger analyses are required. If corroborated in other laboratories, the expression patterns of proteins in this pathway, especially pan-Akt, may be of diagnostic use.