title: CGRRF1 as a novel biomarker of tissue response to metformin in the context of obesity.
abstract: OBJECTIVE
  Obesity-associated hyperestrogenism and hyperinsulinemia contribute significantly to the pathogenesis of endometrial cancer. We recently demonstrated that metformin, a drug long used for treatment of type 2 diabetes, attenuates both insulin- and estrogen-mediated proliferative signaling in the obese rat endometrium. In this study, we sought to identify tissue biomarkers that may prove clinically useful to predict tissue response for both prevention and therapeutic studies. We identified CGRRF1 (cell growth regulator with ring finger domain 1) as a novel metformin-responsive gene and characterized its possible role in endometrial cancer prevention.
  
  
  METHODS
  CGRRF1 mRNA expression was evaluated by RT-qPCR in the endometrium of obese and lean rats, and also in normal and malignant human endometrium. CGRRF1 levels were genetically manipulated in endometrial cancer cells, and its effects on proliferation and apoptosis were evaluated by MTT and Western blot.
  
  
  RESULTS
  CGRRF1 is significantly induced by metformin treatment in the obese rat endometrium. In vitro studies demonstrate that overexpression of CGRRF1 inhibits endometrial cancer cell proliferation. Analysis of human endometrial tumors reveals that CGRRF1 expression is significantly lower in hyperplasia, Grade 1, Grade 2, Grade 3, MMMT, and UPSC endometrial tumors compared to normal human endometrium (p<0.05), suggesting that loss of CGRRF1 is associated with the presence of disease.
  
  
  CONCLUSIONS
  CGRRF1 represents a novel, reproducible tissue marker of metformin response in the obese endometrium. Furthermore, our preliminary data suggests that up-regulation of CGRRF1 expression may prove clinically useful in the prevention or treatment of endometrial cancer.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Celestino
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: McCampbell
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Yates
authors.affiliation: Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Urbauer
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Loose
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Shipley
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: khlu@mdanderson.org.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004714:Endometrial Hyperplasia / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; C103095:CGRRF1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D008687:Metformin
keywords: Estrogen; Insulin resistance; Metformin; Obesity