Biologic targets for therapeutic intervention in endometrioid endometrial adenocarcinoma and malignant mixed müllerian tumors

Objective The purpose of this study was to investigate the AKT signaling cascade in endometrial cancers and to assess its therapeutic potential. Study design Western blotting and immunohistochemistry were used to investigate the expression of estrogen receptor, progesterone receptor, HER2, AKT, and 4EBP1 proteins in 27 atrophic endometria, 31 grade 1 and 24 grade 3 endometrioid endometrial cancers, and 19 malignant mixed müllerian tumors. Inhibition of the AKT signaling cascade was investigated in cell lines. Results Malignant mixed müllerian tumors and grade 3 endometrioid endometrial cancers demonstrated higher levels of AKT and 4EBP1 activation and hormone receptor loss compared with grade 1 endometrioid endometrial cancers and atrophic samples. HER2 over-expression was identified most often in grade 3 tumors without gene amplification. In endometrial cancer cell-lines, AKT cascade inhibitors decreased cell proliferation by apoptosis and cell cycle arrest. Conclusion AKT cascade activation in grade 3 endometrioid endometrial cancers and malignant mixed müllerian tumors is a novel finding. Apoptosis and growth arrest that results from AKT inhibition expose opportunities for therapeutic intervention.