title: Expression of estrogen-induced genes and estrogen receptor β in pancreatic neuroendocrine tumors: implications for targeted therapy.
abstract: OBJECTIVE
  The indolent nature and expression of progesterone receptor (PR), a well-known estrogen-induced gene, in a subset of pancreatic neuroendocrine tumors (PanNETs), raise the possibility of hormonal regulation in these tumors.
  
  
  METHODS
  Immunohistochemical expression of estrogen receptors (ERs) α and β as well as messenger RNA expression of estrogen-induced genes (PR, EIG121, IGF-1, IGF-1R, sFRP1, and sFRP4) by quantitative reverse transcription-polymerase chain reaction were examined in 131 World Health Organization grade G1 and G2 PanNETs and correlated their expression with clinicopathological features.
  
  
  RESULTS
  Thirty-nine PanNETs (30%) showed high positive ERβ staining, and 87 cases (66%) had low positive ERβ staining; only 5 cases (4%) had no nuclear staining. Pancreatic neuroendocrine tumors with small size (P = 0.02), low World Health Organization grade (P = 0.02), and low American Joint Committee on Cancer stage (P = 0.006) more frequently showed high positive ERβ staining. Among the estrogen-induced genes studied, PanNETs had significantly higher expression of PR, EIG121, IGF-1, sFRP1, and sFRP4 compared with normal pancreas, independent of age or sex. High positive ERβ staining was associated with an increased expression of PR (P < 0.001) and EIG121 (P = 0.02).
  
  
  CONCLUSIONS
  Our study showed that PanNETs with favorable prognostic features have higher ERβ expression, which is associated with up-regulated PR and EIG121 messenger RNA expression. Estrogen regulation in PanNETs could potentially help in risk stratification and provide a rational target for novel treatment strategies.
authors: From the Departments of *Pathology, †Biostatistics, and ‡Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Jeannelyn S
authors: JS
authors: Estrella
authors: Ly T
authors: LT
authors: Ma
authors: Denái R
authors: DR
authors: Milton
authors: James C
authors: JC
authors: Yao
authors: Huamin
authors: H
authors: Wang
authors: Asif
authors: A
authors: Rashid
authors: Russell R
authors: RR
authors: Broaddus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000032:analysis; D047629:Estrogen Receptor beta / Q000096:biosynthesis* / Q000235:genetics; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D047368:Tumor Burden; D055815:Young Adult; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D007334:Insulin-Like Growth Factor I; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017526:Receptor, IGF Type 1; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C576597:ATR protein, human