title: Type I interferons modulate methotrexate resistance in gestational trophoblastic neoplasia.
abstract: Resistance to methotrexate is a leading clinical problem in gestational trophoblastic neoplasia (GTN), but there are limited laboratory models for this condition.
  
  
  
  We created isogenic trophoblastic cell lines resistant to methotrexate and compared these to the parent cell lines using gene expression microarrays and qRT-PCR followed by mechanistic studies using recombinant cytokines, pathway inhibitors, and patient sera.
  
  
  
  Gene expression microarrays and focused analysis by qRT-PCR revealed methotrexate led to type I interferon upregulation, in particular interferon alpha 2 (IFNA2), and methotrexate resistance was associated with chronic low level increases in type I interferon expression. Recombinant IFNA2 imparted chemosensitive choriocarcinoma cells with partial resistance to methotrexate, while chemoresistant choriocarcinoma cells were uniquely sensitive to fludarabine, a STAT1 inhibitor. In pre-treatment patient sera, IFNA2 levels correlated with subsequent resistance to methotrexate chemotherapy.
  
  
  
  Methotrexate resistance is influenced by type I interferon signaling with prognostic and therapeutic implications for treating women with GTN.
authors.affiliation: New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Kevin M
authors.identifier: 0000-0003-1502-5553
authors.initials: KM
authors.lastname: Elias
authors.affiliation: Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Campus of Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Harvey
authors.affiliation: New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Kathleen T
authors.initials: KT
authors.lastname: Hasselblatt
authors.affiliation: Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Campus of Imperial College Healthcare NHS Trust, London, UK.|Lung Cancer Biology Group, Division of Medicine, Hammersmith Campus of Imperial College School of Medicine, London, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D005260:Female; D031901:Gestational Trophoblastic Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008727:Methotrexate / Q000494:pharmacology*; D011247:Pregnancy; D059467:Transcriptome
chemical_list: D000964:Antimetabolites, Antineoplastic; D007370:Interferon Type I; D008727:Methotrexate
keywords: chemotherapy resistance; choriocarcinoma; fludarabine; interferon alpha; placenta