Biologic targets for therapeutic intervention in endometrioid endometrial adenocarcinoma and malignant mixed mullerian 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 I and 24 grade 3 endometrioid endometrial cancers, and 19 malignant mixed mullerian tumors. Inhibition of the AKT signaling cascade was investigated in cell lines. Results: Malignant mixed mullerian tumors and grade 3 endometrioid endometrial cancers demonstrated higher levels of AKT and 4EBP1 activation and hormone receptor loss compared with grade I 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 mullerian tumors is a novel finding. Apoptosis and growth arrest that results from AKT inhibition expose opportunities for therapeutic intervention. (C) 2006 Mosby, Inc. All rights reserved.