Clare A Flannery1, Farrah L Saleh1, Gina H Choe1, Daryl J Selen1, Pinar H Kodaman1, Harvey J Kliman1, Teresa L Wood1, Hugh S Taylor1. 1. Obstetrics, Gynecology, and Reproductive Sciences (C.A.F., F.L.S., G.H.C., D.J.S., P.H.K., H.J.K., H.S.T.), Yale School of Medicine, New Haven, Connecticut 06520; Internal Medicine (C.A.F.), Yale School of Medicine, New Haven, Connecticut 06520; and Pharmacology, Physiology and Neuroscience and Cancer Center (T.L.W.), NJ Medical School, Rutgers University, Newark, New Jersey 07101.
Abstract
CONTEXT: Type 2 diabetes and obesity are risk factors for endometrial hyperplasia and cancer, suggesting that hyperinsulinemia contributes to pathogenesis. Insulin action through insulin receptor (IR) splice variants IR-A and IR-B regulates cellular mitogenesis and metabolism, respectively. OBJECTIVE: We hypothesized that IR-A and IR-B are differentially regulated in normal endometrium, according to mitogenic and metabolic requirements through the menstrual cycle, as well as in endometrial hyperplasia and cancer. DESIGN: IR-A, IR-B, and IGF-1 receptor (IGF-1R) mRNA was quantified in endometrium, endometrial epithelial and stromal cells, and in vitro after hormone stimulation. SETTING: Academic center. PATIENTS: Endometrium was collected from women with regular cycles (n = 71), complex hyperplasia (n = 5), or endometrioid adenocarcinoma (n = 11). INTERVENTION(S): In vitro sex-steroid treatment. MAIN OUTCOME MEASURE(S): IR-A and IR-B expression Results: IR-A increased dramatically during the early proliferative phase, 20-fold more than IR-B. In early secretory phase, IR-B and IGF-1R expression increased, reaching maximal expression, whereas IR-A decreased. In adenocarcinoma, IR-B and IGF-1R expression was 5- to 6-fold higher than normal endometrium, whereas IR-A expression was similar to IR-B. Receptor expression was unrelated to body mass index. CONCLUSION: IR-A was elevated during the normal proliferative phase, and in endometrial hyperplasia and adenocarcinoma. The dramatic early rise of IR-A in normal endometrium indicates IR-A is the predominant isoform responsible for initial estrogen-independent endometrial proliferation as well as that of cancer. IR-B is elevated during the normal secretory phase when glucose uptake and glycogen synthesis support embryo development. Differing from other cancers, IR-B expression equals mitogenic IR-A in endometrial adenocarcinoma. Differential IR isoform expression suggests a distinct role for each in endometrial physiology and cancer.
CONTEXT: Type 2 diabetes and obesity are risk factors for endometrial hyperplasia and cancer, suggesting that hyperinsulinemia contributes to pathogenesis. Insulin action through insulin receptor (IR) splice variants IR-A and IR-B regulates cellular mitogenesis and metabolism, respectively. OBJECTIVE: We hypothesized that IR-A and IR-B are differentially regulated in normal endometrium, according to mitogenic and metabolic requirements through the menstrual cycle, as well as in endometrial hyperplasia and cancer. DESIGN:IR-A, IR-B, and IGF-1 receptor (IGF-1R) mRNA was quantified in endometrium, endometrial epithelial and stromal cells, and in vitro after hormone stimulation. SETTING: Academic center. PATIENTS: Endometrium was collected from women with regular cycles (n = 71), complex hyperplasia (n = 5), or endometrioid adenocarcinoma (n = 11). INTERVENTION(S): In vitro sex-steroid treatment. MAIN OUTCOME MEASURE(S): IR-A and IR-B expression Results:IR-A increased dramatically during the early proliferative phase, 20-fold more than IR-B. In early secretory phase, IR-B and IGF-1R expression increased, reaching maximal expression, whereas IR-A decreased. In adenocarcinoma, IR-B and IGF-1R expression was 5- to 6-fold higher than normal endometrium, whereas IR-A expression was similar to IR-B. Receptor expression was unrelated to body mass index. CONCLUSION:IR-A was elevated during the normal proliferative phase, and in endometrial hyperplasia and adenocarcinoma. The dramatic early rise of IR-A in normal endometrium indicates IR-A is the predominant isoform responsible for initial estrogen-independent endometrial proliferation as well as that of cancer. IR-B is elevated during the normal secretory phase when glucose uptake and glycogen synthesis support embryo development. Differing from other cancers, IR-B expression equals mitogenic IR-A in endometrial adenocarcinoma. Differential IR isoform expression suggests a distinct role for each in endometrial physiology and cancer.
Authors: F Frasca; G Pandini; P Scalia; L Sciacca; R Mineo; A Costantino; I D Goldfine; A Belfiore; R Vigneri Journal: Mol Cell Biol Date: 1999-05 Impact factor: 4.272
Authors: B Leibiger; I B Leibiger; T Moede; S Kemper; R N Kulkarni; C R Kahn; L M de Vargas; P O Berggren Journal: Mol Cell Date: 2001-03 Impact factor: 17.970
Authors: Christine Bonnesen; Gitte-Mai Nelander; Bo Falck Hansen; Pia Jensen; Jonas S Krabbe; Marianne B Jensen; Anne Charlotte Hegelund; Jette E Svendsen; Martin B Oleksiewicz Journal: Cell Biol Toxicol Date: 2009-11-08 Impact factor: 6.691
Authors: Clare A Flannery; Gina H Choe; Katherine M Cooke; Andrew G Fleming; Caitlin C Radford; Pinar H Kodaman; Michael J Jurczak; Richard G Kibbey; Hugh S Taylor Journal: J Clin Endocrinol Metab Date: 2018-08-01 Impact factor: 5.958
Authors: Antonino Belfiore; Roberta Malaguarnera; Veronica Vella; Michael C Lawrence; Laura Sciacca; Francesco Frasca; Andrea Morrione; Riccardo Vigneri Journal: Endocr Rev Date: 2017-10-01 Impact factor: 19.871
Authors: Joseph A Dottino; Qian Zhang; David S Loose; Bryan Fellman; Brenda D Melendez; Mikayla S Borthwick; Laurie J McKenzie; Ying Yuan; Richard K Yang; Russell R Broaddus; Karen H Lu; Pamela T Soliman; Melinda S Yates Journal: Am J Obstet Gynecol Date: 2020-08-21 Impact factor: 8.661