Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease.
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.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. jjeong@bcm.tmc.edu
Jae-Wook
JW
Jeong
Hee Sun
HS
Lee
Kevin Y
KY
Lee
Lisa D
LD
White
Russell R
RR
Broaddus
Yu-Wen
YW
Zhang
George F
GF
Vande Woude
Linda C
LC
Giudice
Steven L
SL
Young
Bruce A
BA
Lessey
Sophia Y
SY
Tsai
John P
JP
Lydon
Francesco J
FJ
DeMayo
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000818:Animals; D015536:Down-Regulation; D004714:Endometrial Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D051548:Histone Acetyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D020411:Oligonucleotide Array Sequence Analysis; D011374:Progesterone / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; C475819:Errfi1 protein, mouse; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011374:Progesterone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1