title: The role of TGF-β/Smad signaling in dopamine agonist-resistant prolactinomas.
abstract: BACKGROUND
  Prolactinomas are the most common secretory pituitary adenomas. The first line of treatment involves dopamine agonists (DAs); however, a subset of patients is resistant to such therapy. Recent studies suggest that dopamine can up-regulate TGF-β1 synthesis in rat pituitary lactotrophs whereas estradiol down-regulates TGF-β1. To date, the role of TGF-β/Smad signaling in DAs-resistant prolactinomas has not been explored.
  
  
  METHODS
  High-content screening (HCS) techniques, qRT-PCR, Western blot, immunofluorescence and ELISA, were performed to determine the role of TGF-β/Smad signaling in DAs-resistant prolactinomas.
  
  
  RESULTS
  We reported a significant down-regulation of TGF-β/Smad signaling cascade in DAs-resistant prolactinomas compared to normal human anterior pituitaries. Following treatment with TGF-β1, the dopamine agonist, bromocriptine, and the estrogen antagonist (ER), fulvestrant in GH3 cells, we found that TGF-β1 and fulvestrant caused significant cytotoxicity in a dose- and time-dependent manner and activated Smad3 was detected following exposure to TGF-β1 and fulvestrant. In addition, treating GH3 cells with fulvestrant increased active TGF-β1 levels and decreased PRL levels in a dose-dependent manner.
  
  
  CONCLUSIONS
  TGF-β/Smad signaling pathway may play an important role in DA-resistant prolactinomas and has the potential to be a viable target for the diagnosis and treatment of prolactinomas, particularly in patients who are resistant to DAs.
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Zhenye
authors.initials: Z
authors.lastname: Li
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Chuzhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Xuyi
authors.initials: X
authors.lastname: Zong
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Bai
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Youtu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Lan
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China. Electronic address: zyz2004520@yeah.net.
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001971:Bromocriptine / Q000494:pharmacology; D045744:Cell Line, Tumor; D018491:Dopamine Agonists / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015175:Prolactinoma / Q000188:drug therapy / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D018491:Dopamine Agonists; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D000077267:Fulvestrant; D001971:Bromocriptine; D004958:Estradiol
keywords: Dopamine agonist-resistant; Estrogen receptor antagonist; Prolactinomas; Smad3; TGF-β