title: An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer.
abstract: BACKGROUND
  Transforming growth factor-βs (TGF-βs) play a dual role in breast cancer, with context-dependent tumor-suppressive or pro-oncogenic effects. TGF-β antagonists are showing promise in early-phase clinical oncology trials to neutralize the pro-oncogenic effects. However, there is currently no way to determine whether the tumor-suppressive effects of TGF-β are still active in human breast tumors at the time of surgery and treatment, a situation that could lead to adverse therapeutic responses.
  
  
  METHODS
  Using a breast cancer progression model that exemplifies the dual role of TGF-β, promoter-wide chromatin immunoprecipitation and transcriptomic approaches were applied to identify a core set of TGF-β-regulated genes that specifically reflect only the tumor-suppressor arm of the pathway. The clinical significance of this signature and the underlying biology were investigated using bioinformatic analyses in clinical breast cancer datasets, and knockdown validation approaches in tumor xenografts.
  
  
  RESULTS
  TGF-β-driven tumor suppression was highly dependent on Smad3, and Smad3 target genes that were specifically enriched for involvement in tumor suppression were identified. Patterns of Smad3 binding reflected the preexisting active chromatin landscape, and target genes were frequently regulated in opposite directions in vitro and in vivo, highlighting the strong contextuality of TGF-β action. An in vivo-weighted TGF-β/Smad3 tumor-suppressor signature was associated with good outcome in estrogen receptor-positive breast cancer cohorts. TGF-β/Smad3 effects on cell proliferation, differentiation and ephrin signaling contributed to the observed tumor suppression.
  
  
  CONCLUSIONS
  Tumor-suppressive effects of TGF-β persist in some breast cancer patients at the time of surgery and affect clinical outcome. Carefully tailored in vitro/in vivo genomic approaches can identify such patients for exclusion from treatment with TGF-β antagonists.
authors.forename: Misako
authors.initials: M
authors.lastname: Sato
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Kadota
authors.forename: Binwu
authors.initials: B
authors.lastname: Tang
authors.forename: Howard H
authors.initials: HH
authors.lastname: Yang
authors.forename: Yu-an
authors.initials: YA
authors.lastname: Yang
authors.forename: Mengge
authors.initials: M
authors.lastname: Shan
authors.forename: Jia
authors.initials: J
authors.lastname: Weng
authors.forename: Michael A
authors.initials: MA
authors.lastname: Welsh
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Flanders
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagano
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Michalowski
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Clifford
authors.forename: Maxwell P
authors.initials: MP
authors.lastname: Lee
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D036342:Ephrins / Q000378:metabolism; D005260:Female; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D036104:Receptor, EphA2 / Q000378:metabolism; D051899:Smad2 Protein / Q000235:genetics; D051900:Smad3 Protein / Q000096:biosynthesis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D036342:Ephrins; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D036104:Receptor, EphA2