Diseases of the female reproductive tract represent a significant women's health problem. Endometrial cancer is the most common gynecologic malignancy and the fourth most common cancer in women. Additionally, endometriosis affects an estimated 5 million women in the US and is commonly associated with infertility and pelvic pain. One of the major hallmarks of uterine diseases is disruption of steroid hormone control of uterine cell proliferation and differentiation. Using high density DNA microarray analysis, we have identified Mig-6 in the uterus as a target of SRC-1 and PR. Mig-6 regulates mouse fertility and the ability of P4 to attenuate E2 signaling using total and conditional ablation of Mig-6. The expression of Mig-6 in both level and cell specificity is dependent upon the menstrual cycle in the human endometrium. The expression of Mig- 6 is decreased in human endometriosis and endometrial cancer patients. The overall hypothesis of this proposal is that Mig-6 mediates the ability of P4 to inhibit endometrial cell proliferation caused by E2. The goal of this proposal will be to investigate the role of Mig-6 in the regulation of uterine endometrial function.
Specific Aim 1 will investigate the role of Mig-6 in fertility and uterine physiology by the determination of the cell type specific expression and endocrine regulation of Mig-6 in the murine uterus and the characterization of the phenotype of mice with conditional ablation of Mig-6 in the reproductive tract.
Specific Aim 2 will investigate the role of Mig-6 in the steroid regulation of uterine cell proliferation and gene expression.
Specific Aim 3 will investigate the endometrial compartment in which Mig-6 regulates endometrial steroid responsiveness by using the tissue recombination technique. The understanding of the role of Mig-6 in steroid hormone regulation, early pregnancy, proliferation, and apoptosis of the uterus will provide a strategy to develop diagnostic and therapeutic tools for infertility, endometriosis, and endometrial cancer.

Public Health Relevance

The expression of Mig-6 is decreased in human endometriosis and endometrial cancer patients. The goal of this proposal will be to investigate the role of Mig-6 in the regulation of steroid hormones in uterine endometrium function. The understanding of the role of Mig-6 in steroid hormone regulation, early pregnancy, proliferation, and apoptosis of the uterus will provide a strategy to develop diagnostic and therapeutic tools for infertility, endometriosis, and endometrial cancer.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD057873-06
Application #
8249345
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$248,007
Indirect Cost
$86,439
Name
Michigan State University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Kim, Tae Hoon; Yoo, Jung-Yoon; Kim, Hong Im et al. (2014) Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation. Cancer Res 74:7371-82
Jeong, Jae-Wook (2014) In search of molecular mechanisms in endometriosis. Endocrinology 155:1178-80
Kim, Tae Hoon; Yu, Yanni; Luo, Lily et al. (2014) Activated AKT pathway promotes establishment of endometriosis. Endocrinology 155:1921-30
Yoo, Jung-Yoon; Shin, Heesung; Kim, Tae Hoon et al. (2014) CRISPLD2 is a target of progesterone receptor and its expression is decreased in women with endometriosis. PLoS One 9:e100481
Lee, Jae Hee; Kim, Tae Hoon; Oh, Seo Jin et al. (2013) Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. FASEB J 27:2553-63
Oh, Seo Jin; Shin, Jung-Ho; Kim, Tae Hoon et al. (2013) *-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition. J Pathol 231:210-22
Oh, Seo Jin; Kim, Tae Hoon; Lim, Jeong Mook et al. (2013) Progesterone induces expression of Lrp2 in the murine uterus. Biochem Biophys Res Commun 441:175-9
Kim, Tae Hoon; Lee, Dong-Kee; Cho, Sung-Nam et al. (2013) Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer. Cancer Res 73:5090-9
Afshar, Yalda; Jeong, Jae-Wook; Roqueiro, Damian et al. (2012) Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J 26:282-94
Franco, Heather L; Rubel, Cory A; Large, Michael J et al. (2012) Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J 26:1218-27

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