title: Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices.
abstract: OBJECTIVE
  To examine hormone receptor expression levels and downstream gene activation in pre-treatment and post-treatment biopsies in a cohort of patients with endometrial pathology who were being conservatively managed with a progestin-containing intrauterine device (IUD). A molecular signature of treatment failure is proposed.
  
  
  METHODS
  A retrospective analysis of pre- and post-treatment biopsy specimens from 10 women treated with progestin-containing IUD for complex atypical hyperplasia (CAH) or grade 1 endometrioid adenocarcinoma was performed. Expression of estrogen receptor (ER), progesterone receptor (PR) and PR target genes was examined by immunohistochemistry (IHC) and quantitative RT-PCR.
  
  
  RESULTS
  The mean treatment duration was 14.3 months. Four CAH patients had stable disease or regressed after treatment, and four progressed to endometrioid adenocarcinoma. Both patients with an initial diagnosis of endometrioid adenocarcinoma regressed to CAH or no disease. In general, hormone receptor levels diminished post-treatment compared to pre-treatment biopsies; however, we noted unexpected higher expression of the B isoform of PR (PRB) as well as ER in those patients who progressed to frank cancer. There was a trend towards a non-nuclear cytoplasmic location of PRB in these patients. Importantly, the differentiating impact of PR signaling, as determined by the expression of the progestin-controlled tumor suppressor FOXO1, was lost in individuals who progressed on therapy.
  
  
  CONCLUSIONS
  FOXO1 mRNA levels may serve as a biomarker for response to therapy and an indicator of PR function in patients being conservatively managed with a progestin-containing IUD.
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: henry-reyes@uiowa.edu.
authors.forename: Henry D
authors.initials: HD
authors.lastname: Reyes
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Matthew.Carlson@utsouthwestern.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Carlson
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: eric-devor@uiowa.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Devor
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Yuping-zhang@uiowa.edu.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Kristina-thiel@uiowa.edu.
authors.forename: Kristina W
authors.initials: KW
authors.lastname: Thiel
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: megan-samuelson@uiowa.edu.
authors.forename: Megan I
authors.initials: MI
authors.lastname: Samuelson
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: megan-e-mcdonald@uiowa.edu.
authors.forename: Megan
authors.initials: M
authors.lastname: McDonald
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Department of Pathology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Shujie-yang@uiowa.edu.
authors.forename: Shujie
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: jean-marie-stephan@uiowa.edu.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Stephan
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: savagee2@ccf.org.
authors.forename: Erica C
authors.initials: EC
authors.lastname: Savage
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Donghai-dai@uiowa.edu.
authors.forename: Donghai
authors.initials: D
authors.lastname: Dai
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Michael-goodheart@uiowa.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goodheart
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Kimbery-Leslie@uiowa.edu.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
mesh_terms: D000328:Adult; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D015536:Down-Regulation; D004714:Endometrial Hyperplasia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D007436:Intrauterine Devices, Medicated; D008875:Middle Aged; D011237:Predictive Value of Tests; D011372:Progestins / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D012189:Retrospective Studies
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011372:Progestins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
keywords: Endometrial cancer; Endometrial hyperplasia; FOXO1; Progesterone receptor; Progestin-containing intrauterine devices