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

Abstract

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.estrogen ͉ endometrial cancer ͉ progesterone ͉ progesterone receptor ͉ SRC-1

Mig-6 controls EGFR trafficking and suppresses gliomagenesis

“…1 D and E). Whereas PARK7 is an oncogene that inhibits the PTEN tumor suppressor (25)(26)(27)), Mig-6 shows many properties consistent with a tumor suppressor role including cancer-prone phenotypes in knockout mice (12,13,28). In the context of this study, it is notable that Mig-6 was identified as a mitogen-inducible gene and is a presumed adaptor protein linked to the regulation of a variety of signaling pathways, including the key GBM oncogene EGFR (8)(9)(10)(11).…”

Elevated Serum Levels of Estradiol Induce Endometrial Hyperplasia Rather than Carcinoma in a Mouse Model Using a Carcinogen

“…Vilgelm et al found that the number of endometrial carcinoma lesions in Pten-/+ mice was reduced by the administration of a pure ERα antagonist, suggesting a positive role of estrogen in tumorigenesis [21]. Jeong et al reported that the knockout of MIG6, a pivotal downstream molecule in the progestin-induced growth suppression of endometrial carcinoma cells, resulted in the development of endometrial carcinoma following the addition of E2 [22]. In contrast, Joshi et al showed that Pten-/+ mice developed endometrial carcinoma, whereas the simultaneous knockout of ERα resulted in a higher incidence of endometrial carcinoma, suggesting that endometrial carcinogenesis is independent of estrogen and ERα [23].…”

Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France

“…Thus, studies focused on gene regulation using transgenic models will provide valuable insights into mechanisms that may contribute to endometriosis. 116,117,111 Recommendation. Targeted gene knockout and transgenic models should be employed to investigate the function of genes in the context of endometriosis.…”