title: Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors.
abstract: Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology.
  
  
  
  We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively.
  
  
  
  In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01).
  
  
  
  These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK. m.merritt@imperial.ac.uk.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Merritt
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Strickler
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.|Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Einstein
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.
authors.forename: Hannah P
authors.initials: HP
authors.lastname: Yang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.|Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
authors.forename: Jurriaan
authors.initials: J
authors.lastname: Brouwer-Visser
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Cossio
authors.affiliation: Department of Pathology, Jack D. Weiler Hospital, The University Hospital for Albert Einstein College of Medicine, Montefiore Medical Center, 1825 Eastchester Road, Room 338, Bronx, NY, 10461, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Whitney
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Gunter
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
authors.forename: Gloria S
authors.initials: GS
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D004717:Endometrium / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010298:Parity; D010750:Phosphoproteins / Q000378:metabolism; D017698:Postmenopause; D017697:Premenopause; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D012739:Gonadal Steroid Hormones; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; C032231:IGFBP1 protein, human; C515497:IGFBP3 protein, human; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D010750:Phosphoproteins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Endometrial cancer; Endometrium; Estrogen receptor; Insulin; Insulin-like growth factor