Significance of Akt activation and AKT gene increases in soft tissue tumors.

To clarify the aberrations of AKT genes, their protein products and clinicopathologic significance in bone and soft tissue tumors, expression profiles of total Akt, its isoforms and activated Akt, and increases in copy number of AKT1/AKT2 genes were examined. Immunohistochemical analysis in 77 cases revealed overexpression of total Akt, Akt1, Akt2, and phosphorylated Akt in 84.4%, 67.5%, 72.7%, and 71.4%, respectively. Positive results were also observed in benign lesions but at a lower frequency. Overexpression of Akt1 was more frequent than that of Akt2 in well-differentiated liposarcoma (6/7 versus 3/7 cases) and schwannoma (4/4 versus 1/4 cases), whereas Akt2 overexpression and Akt activation were more frequent than Akt1 overexpression in malignant nerve sheath (3/4 and 4/4, respectively, versus 2/4 cases) and muscular tumors (8/9 and 8/9 versus 4/9 cases). By fluorescence in situ hybridization analysis, increase of gene copy number was observed in 13.3% for AKT1 and in 25.0% for AKT2 due to polysomy of chromosome 14 or 19, respectively, but not gene amplification. One case of schwannoma exhibited polysomy of both chromosomes 14 and 19. Akt activation was correlated with total Akt cytoplasmic localization (P = .0031) and subsequent metastasis (P = .0454). Moreover, AKT2 gene increase correlated with tumor size (P = .0352) and metastasis (P = .0344). In conclusion, in a defined subset of bone and soft tissue tumors, including benign tumors, Akt was frequently overexpressed and activated, and AKT1/2 copy number was increased. Because abnormality of Akt/AKT correlated with clinicopathologic profiles, novel therapies targeting isoform-specific Akts may be useful for these particular types of tumors.