title: The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in visceral adipocytes predicts endometrial cancer progression and patient survival.
abstract: OBJECTIVE
  Currently, accurately identifying endometrial cancer patients at high risk for recurrence remains poor. To ascertain if changes in the endoplasmic reticulum (ER) stress marker, glucose-regulated-protein-78 (GRP78) can serve as a prognosticator in endometrial cancer, we examined GRP78 expression in patient samples to determine its association with clinical outcome.
  
  
  METHODS
  A retrospective cohort study was conducted in endometrial cancer patients. Archived specimens of visceral adipocytes and paired endometrial tumors were analyzed by immunohistochemistry for GRP78 and another ER stress marker, C/EBP homologous protein (CHOP). Expression of these markers was correlated with clinico-pathological information and outcomes.
  
  
  RESULTS
  GRP78 expression in visceral adipocytes was detected in 95% of the 179 endometrial cancer patients with analyzable visceral adipocytes. Within individual samples, 24% of adipocytes (range, 0-90%, interquartile range 18%-38%) exhibited GRP78 expression. High visceral adipocyte GRP78 expression positively correlated with advanced-stage disease (p=0.007) and deep myometrial invasion (p=0.004). High visceral adipocyte GRP78 expression was significantly associated with decreased disease-free survival (DFS) in multivariate analyses (hazard ratio 2.88, 95% CI 1.37-6.04, p=0.005). CHOP expression paralleled the GRP78 expression in adipocytes (r=0.55, p<0.001) and in the tumor (p=0.018).
  
  
  CONCLUSIONS
  Our study demonstrates that the ER stress markers, GRP78 and CHOP, are elevated in endometrial cancer patients. Furthermore, GRP78 expression levels in visceral adipocytes from these patients were significantly correlated to disease stage and patient survival. Our results demonstrate, for the first time, that the GRP78 levels in endometrial cancer patients may be a prognosticator and aid with clinical risk stratification and focused surveillance.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gray
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Yang
authors.forename: Sucheta A
authors.initials: SA
authors.lastname: Srivastava
authors.forename: Prem B
authors.initials: PB
authors.lastname: Tripathi
authors.forename: Laura A
authors.initials: LA
authors.lastname: Sonoda
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Yoo
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Lin
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins