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.


METHODS
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.


CONCLUSIONS
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.
Rice
Laurel W
LW
Norman Thornton Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Health System, Charlottesville, VA 22908, USA. lwr9y@virginia.edu
Stone
Rebecca L
RL
Xu
Miaohou
M
Galgano
Mary
M
Stoler
Mark H
MH
Everett
Elise N
EN
Jazaeri
Amir A
AA
D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D018200:Mixed Tumor, Mullerian / Q000188:drug therapy* / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000502:physiology
D051058:Oncogene Protein v-akt