title: Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Academic center.
  
  
  
  Endometrium was collected from women with regular cycles (n = 71), complex hyperplasia (n = 5), or endometrioid adenocarcinoma (n = 11).
  
  
  
  In vitro sex-steroid treatment.
  
  
  
  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.
  
  
  
  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.affiliation: 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.
authors.forename: Clare A
authors.initials: CA
authors.lastname: Flannery
authors.affiliation: 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.
authors.forename: Farrah L
authors.initials: FL
authors.lastname: Saleh
authors.affiliation: 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.
authors.forename: Gina H
authors.initials: GH
authors.lastname: Choe
authors.affiliation: 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.
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Selen
authors.affiliation: 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.
authors.forename: Pinar H
authors.initials: PH
authors.lastname: Kodaman
authors.affiliation: 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.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Kliman
authors.affiliation: 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.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wood
authors.affiliation: 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.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Taylor
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004714:Endometrial Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008597:Menstrual Cycle / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015703:Antigens, CD; D021122:Protein Subunits; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin