Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease
Open accessAbstract
Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) effects. An imbalance caused by increased E2 action and/or decreased P4 action can result in abnormal endometrial proliferation and, ultimately, endometrial adenocarcinoma, the fourth most common cancer in women. We have identified mitogen-inducible gene 6 ( Mig-6 ) as a downstream target of progesterone receptor (PR) and steroid receptor coactivator (SRC-1) action in the uterus. Here, we demonstrate that absence of Mig-6 in mice results in the inability of P4 to inhibit E2-induced uterine weight gain and E2-responsive target genes expression. At 5 months of age, the absence of Mig-6 results in endometrial hyperplasia. Ovariectomized Mig-6 d/d mice exhibit this hyperplastic phenotype in the presence of E2 and P4 but not without ovarian hormone. Ovariectomized Mig-6 d/d mice treated with E2 developed invasive endometrioid-type endometrial adenocarcinoma. Importantly, the observation that endometrial carcinomas from women have a significant reduction in MIG-6 expression provides compelling support for an important growth regulatory role for Mig-6 in the uterus of both humans and mice. This demonstrates the Mig-6 is a critical regulator of the response of the endometrium to E2 in regulating tissue homeostasis. Since Mig-6 is regulated by both PR and SRC-1, this identifies a PR, SRC-1, Mig-6 regulatory pathway that is critical in the suppression of endometrial cancer.
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It is becoming increasingly evident that altered expression of genes in a pathological context contributes to many of the biological processes that are dysregulated in endometriosis, including cell proliferation, inhibition of apoptosis, and altered hormonal sensitivity.
“It is becoming increasingly evident that altered expression of genes in a pathological context contributes to many of the biological processes that are dysregulated in endometriosis, including cell proliferation, inhibition of apoptosis, and altered hormonal sensitivity.”
From Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France (2013) · cites this paper as [116]
Studies focused on gene regulation using transgenic models will provide valuable insights into mechanisms that may contribute to endometriosis.
“Thus, studies focused on gene regulation using transgenic models will provide valuable insights into mechanisms that may contribute to endometriosis.116,117,111”
From Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France (2013) · cites this paper as [116]
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Progesterone: the ultimate endometrial tumor suppressor
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- Authors
- Jeong, J.-W., Lee, H. S., Lee, K. Y., White, L. D., Broaddus, R. R., Zhang, Y.-W., Vande Woude, G. F., Giudice, L. C., Young, S. L., Lessey, B. A., Tsai, S. Y., Lydon, J. P., & DeMayo, F. J.
- Affiliations
- Baylor College of Medicine (US)
- MizMedi Hospital (KR)
- The University of Texas MD Anderson Cancer Center (US)
- Van Andel Institute (US)
- Laboratories of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503;
- University of California, San Francisco (US)
- University of North Carolina at Chapel Hill (US)
- Prisma Health (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-05-26
- Volume
- 106
- Issue
- 21
- Pages
- 8677-8682
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2681319
- OpenAlex
- W2058910623
- Cited by
- 92
- References
- 49
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 1 · 2022: 7 · 2021: 3 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 8 · 2014: 15 · 2013: 7 · 2012: 3
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (U54HD0077495, BCTR0503763)
- National Cancer Institute (P50CA098258, R01-CA7753, R01CA077530)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54 HD-0077495, U01HD042311, U54HD035041, R03HD077495, R01HD057873)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- MIG6, endometrial adenocarcinoma, endometrial hyperplasia, progesterone receptor, SRC-1, progesterone, ovariectomy
- MeSH terms
- Adolescent, Adult, Animals, Endometrial Hyperplasia, Estrogens, Female, Humans, Progesterone, Transcription Factors, Down-Regulation, Endometrial Neoplasms, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Histone Acetyltransferases, Nuclear Receptor Coactivator 1
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