title: Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels.
abstract: OBJECTIVE
  Dopamine agonists normalize prolactin (PRL) levels and reduce tumour size in responsive prolactinoma. However, several cases have shown resistance to dopamine agonists upon initial treatment. Infrequently, prolactinoma initially responds, but then becomes refractory to prolonged treatment (secondary resistance). We investigated the possible mechanisms of resistance to dopamine agonists.
  
  
  METHODS
  Twelve cases of prolactinoma were surgically resected and classified according to the responsiveness of PRL levels and tumour size to dopamine agonists: good responders (n = 5), poor responders (n = 5), or secondary resistance (n = 2). We examined the expression of dopamine D(2) receptor (D(2)R) isoform (short: D(2)S and long: D(2)L) mRNA and protein. We investigated DNA methylation patterns in the promoter region of the DRD2 gene.
  
  
  RESULTS
  The predominant D(2)R isoform expressed in prolactinoma was D(2)L. Levels of D(2)L mRNA were significantly lower in secondary resistance and poor responders than in good responders. Expression of D(2)R protein was variable among cases. Almost no CpG sites of the DRD2 gene promoter region were methylated.
  
  
  CONCLUSIONS
  Resistance of prolactinoma to dopamine agonists is correlated with a reduction in D(2)L isoform mRNA levels. Silencing of the DRD2 gene by methylation in the promoter region is unlikely to play a role in dopamine agonist resistance in prolactinoma.
authors: Division of Familial Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. sshimazu@ncc.go.jp
authors: Satoko
authors: S
authors: Shimazu
authors: Akira
authors: A
authors: Shimatsu
authors: Shozo
authors: S
authors: Yamada
authors: Naoko
authors: N
authors: Inoshita
authors: Yuko
authors: Y
authors: Nagamura
authors: Takeshi
authors: T
authors: Usui
authors: Toshihiko
authors: T
authors: Tsukada
mesh_terms: D000328:Adult; D018491:Dopamine Agonists / Q000627:therapeutic use*; D065127:Dopamine D2 Receptor Antagonists; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015175:Prolactinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D059368:RNA Isoforms / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult
chemical_list: D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D059368:RNA Isoforms; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor