Critical Tumor Suppressor Function Mediated by Epithelial Mig-6 in Endometrial Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 16; pp. 5090 - 5099
• Main Authors: TAE HOON KIM, LEE, Dong-Kee, CHO, Sung-Nam, ORVIS, Grant D, BEHRINGER, Richard R, LYDON, John P, BON JEONG KU, McCAMPBELL, Adrienne S, BROADDUS, Russell R, JEONG, Jae-Wook
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2013
• Subjects: Animals; Antineoplastic agents; Apoptosis - physiology; Baculoviral IAP Repeat-Containing 3 Protein; Biological and medical sciences; Cell Growth Processes - physiology; Endometrial Hyperplasia - genetics; Endometrial Hyperplasia - metabolism; Endometrial Hyperplasia - pathology; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Endometrial Neoplasms - prevention & control; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium - metabolism; Epithelium - pathology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens - genetics; Estrogens - metabolism; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Mice; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Progesterone - genetics; Progesterone - metabolism; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Stromal Cells - metabolism; Stromal Cells - pathology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Ubiquitin-Protein Ligases; Uterus - metabolism; Uterus - pathology; Wnt Proteins - genetics; Wnt Proteins - metabolism; Endometrium cancer; CXCL9 chemokine; Uterine diseases; Malignant tumor; CXC chemokine; Cancer; Female genital diseases; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-0241

Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6(f/f)) mice were crossed to Wnt7a-Cre mice (Wnt7a(cre+)Mig-6(f/f)). Wnt7a(cre+)Mig-6(f/f) mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7a(cre+)Mig-6(f/f) mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7a(cre+)Mig-6(f/f) mice was prevented by progesterone treatment, whereas this treatment had no effect in PR(cre/+)Mig-6(f/f) mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer.