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 #
5R01HD057873-03
Application #
7800462
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
2008-04-01
Project End
2011-01-20
Budget Start
2010-04-01
Budget End
2011-01-20
Support Year
3
Fiscal Year
2010
Total Cost
$228,304
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Evans-Hoeker, Emily; Lessey, Bruce A; Jeong, Jae Wook et al. (2016) Endometrial BCL6 Overexpression in Eutopic Endometrium of Women With Endometriosis. Reprod Sci 23:1234-41
Rubel, Cory A; Wu, San-Pin; Lin, Lin et al. (2016) A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function. Cell Rep 17:1414-1425
Yoo, Jung-Yoon; Kim, Tae Hoon; Kong, Sieun et al. (2016) Role of Mig-6 in hepatic glucose metabolism. J Diabetes 8:86-97
Joung, Kyong Hye; Jeong, Jae-Wook; Ku, Bon Jeong (2015) The association between type 2 diabetes mellitus and women cancer: the epidemiological evidences and putative mechanisms. Biomed Res Int 2015:920618
Kim, Tae Hoon; Yoo, Jung-Yoon; Wang, Zhong et al. (2015) ARID1A Is Essential for Endometrial Function during Early Pregnancy. PLoS Genet 11:e1005537
Kim, Byung Gak; Yoo, Jung-Yoon; Kim, Tae Hoon et al. (2015) Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis. Hum Reprod 30:1069-78
Yoo, Jung-Yoon; Kim, Tae Hoon; Lee, Jae Hee et al. (2015) Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling. Biochem Biophys Res Commun 462:409-14
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

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