title: Up-regulation of genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in the endometrium may link polycystic ovarian syndrome and endometrial cancer.
abstract: BACKGROUND
  Endometrial cancer (EC) is the most common gynaecological cancer amongst women in the UK. Although previous studies have found that women with polycystic ovary syndrome (PCOS) have at least a three-fold increase in endometrial cancer (EC) risk compared to women without PCOS, the precise molecular mechanisms which link between PCOS and EC remain unclear. It has been suggested that insulin resistance may contribute to the increased risk of EC in PCOS. The specific expression of genes related to the insulin-signalling pathway including the IGF system in the endometrium of women with PCOS has however never been measured and compared to that in women with EC without PCOS and control women without EC or PCOS. .
  
  
  OBJECTIVE
  To test the hypothesis that insulin signalling plays a key role in the development of EC in women with PCOS by measuring and comparing the expression of three key genes involved in the insulin signalling pathway (IGF1, PTEN and IGFBP1) in endometrial tissue obtained from three groups of women; PCOS without EC, women with EC without PCOS and non-PCOS women without EC (controls). We also aimed to determine the correlation between the gene expressions to various clinical variables among participants.
  
  
  METHODS
  This was a cross-sectional study of 102 women in 3 groups (PCOS, EC and controls) at a University teaching hospital in the United Kingdom. Clinical assessment (blood pressure, body mass index (BMI) and waist-hip-circumference ratio), venepuntures (fasting blood sugar, insulin, lipid profile, hormones) and endometrial tissue biopsies were taken in all participants. Endometrial tissue RNA extraction was performed before real time polymerase-chain-reaction for the genes of interest (IGF1, IGFBP1 and PTEN) was carried out. To compare the baseline characteristics of the study population, One-Way-ANOVA test or the Independent t-test was used. For variables that were not normally distributed, the Spearman correlation test was used to calculate the r value. A "p" value of <0.05 was considered statistically significant.
  
  
  RESULTS
  IGF1, IGFBP1 and PTEN gene expression were significantly up-regulated in the endometrium of PCOS and EC women compared to controls. However there was no significant difference in the expression of these genes in PCOS compared to EC endometrium. The BMI of women with PCOS and controls, were not significantly different (29.28 (± 2.91) vs 28.58 (± 2.62) kg/m(2)) respectively, women with EC however had a higher mean BMI (32.22 (± 5.70) kg/m(2)). PCOS women were younger (31.8 (± 5.97) years) than women with EC (63.44 (± 10.07) years) and controls (43.68 (± 13.12) years). The changes in gene expression were independent of BMI, waist hip ratio, estradiol and androgen levels. Protein validation test in the serum samples in the three groups were consistent with the gene findings.
  
  
  CONCLUSIONS
  Women with PCOS and EC have an increased endometrial expression of genes (IGF1, IGFBP1 and PTEN) involved in the insulin signalling pathway compared with control women. This may explain the increased risk of EC in PCOS women. This study provides a strong basis for clinical trials aiming to prevent EC in women with PCOS by investigating drugs targeting the insulin signalling pathway. This panel of genes may also serve as clinically useful early biomarkers which predict which women with PCOS will go on to develop EC.
authors.affiliation: Division of Obstetrics and Gynaecology and Child Health, School of Medicine, Faculty of Medicine and Health Sciences, Queen's Medical Centre, Nottingham University Hospital, Derby Road, Nottingham, NG7 2UH, UK; Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia, Faculty of Medicine, Cheras, Kuala Lumpur, 56000, Malaysia. Electronic address: mgxmnsh@nottingham.ac.uk.
authors.forename: Mohamad Nasir
authors.initials: MN
authors.lastname: Shafiee
authors.affiliation: Department of Haematology, Clinical Sciences Building, University of Nottingham, Hucknall Road, Nottingham, NG5 1PB, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Seedhouse
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, LE12 5RD, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mongan
authors.affiliation: Division of Medical Sciences and Graduate Entry Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, NG5 1PB, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Chapman
authors.affiliation: Department of Pathology, Queen's Medical Centre, Nottingham University Hospital, Nottingham, NG7 2UH, UK.
authors.forename: Suha
authors.initials: S
authors.lastname: Deen
authors.affiliation: Department of Obstetrics and Gynaecology, City Hospital, Nottingham University Hospital, Nottingham, NG5 1PB, UK.
authors.forename: Jafaru
authors.initials: J
authors.lastname: Abu
authors.affiliation: Division of Obstetrics and Gynaecology and Child Health, School of Medicine, Faculty of Medicine and Health Sciences, Queen's Medical Centre, Nottingham University Hospital, Derby Road, Nottingham, NG7 2UH, UK.
authors.forename: William
authors.initials: W
authors.lastname: Atiomo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008875:Middle Aged; D018832:Molecular Chaperones; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490467:IGBP1 protein, human; C583557:IGF1 protein, human; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D007334:Insulin-Like Growth Factor I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Endometrial cancer; IGF1; IGFBP1; PCOS; PTEN