Biologic targets for therapeutic intervention in endometrioid endometrial adenocarcinoma and malignant mixed müllerian tumors - 18/08/11

Doi : 10.1016/j.ajog.2005.12.020

Laurel W. Rice, MD ^a,^⁎ , Rebecca L. Stone, MD ^a, Miaohou Xu, MD, PhD ^a, Mary Galgano, MD ^b, Mark H. Stoler, MD ^b, Elise N. Everett, MD ^a, Amir A. Jazaeri, MD ^a
^a Departments of Obstetrics and Gynecology, Norman Thornton Division of Gynecologic Oncology
^b Department of Pathology, University of Virginia Health System, Charlottesville, VA

Reprint requests: Laurel W. Rice, MD, University of Virginia Health System, Box 800712, Charlottesville, VA 22908.

Abstract

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.

Le texte complet de cet article est disponible en PDF.

Key words : Malignant mixed müllerian tumor, Endometrial cancer, AKT, mTOR

Plan

Material and methods

Human tissue samples

Tissue arrays

Cell culture and growth studies

Apoptosis enzyme-linked immunosorbent assay

Statistical analysis

Results

ER⍺ protein expression lost in G3 and MMMT

HER2 protein overexpressed in G3 tumors without DNA amplification

AKT and 4EBP1 significantly activated in G3 and poorly differentiated endometrial cancers

Targeted inhibition of PI3K-AKT-mTOR pathway alters proliferation and survival in endometrial cancer cells

HER2-targetted therapy does not affect cell growth or apoptosis

Comment

Supported by the University of Virginia Cancer Center P30 CA44579 and donors.
Presented at the Twenty-Fourth Annual Meeting of the American Gynecological and Obstetrical Society, September 29-October 1, 2005, Victoria, British Columbia, Canada.