Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Proc Natl Acad Sci U S A. 2009 May 26;106(21):8677-82. doi: 10.1073/pnas.0903632106. Epub 2009 May 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adolescent
  • Adult
  • Animals
  • Down-Regulation
  • Endometrial Hyperplasia / genetics
  • Endometrial Hyperplasia / metabolism*
  • Endometrial Hyperplasia / pathology
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / metabolism*
  • Endometrial Neoplasms / pathology
  • Estrogens / metabolism*
  • Female
  • Histone Acetyltransferases / deficiency
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Coactivator 1
  • Oligonucleotide Array Sequence Analysis
  • Progesterone / metabolism*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins


  • Adaptor Proteins, Signal Transducing
  • ERRFI1 protein, human
  • Errfi1 protein, mouse
  • Estrogens
  • Intracellular Signaling Peptides and Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Progesterone
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1