title: The histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression.
abstract: OBJECTIVE
  Cancer stem cells (CSC) are the tumorigenic cell population that has been shown to sustain tumor growth and to resist conventional therapies. The purpose of this study was to evaluate the potential of histone deacetylase inhibitors (HDACi) as anti-CSC therapies.
  
  
  METHODS
  We evaluated the effect of the HDACi compound abexinostat on CSCs from 16 breast cancer cell lines (BCL) using ALDEFLUOR assay and tumorsphere formation. We performed gene expression profiling to identify biomarkers predicting drug response to abexinostat. Then, we used patient-derived xenograft (PDX) to confirm, in vivo, abexinostat treatment effect on breast CSCs according to the identified biomarkers.
  
  
  RESULTS
  We identified two drug-response profiles to abexinostat in BCLs. Abexinostat induced CSC differentiation in low-dose sensitive BCLs, whereas it did not have any effect on the CSC population from high-dose sensitive BCLs. Using gene expression profiling, we identified the long noncoding RNA Xist (X-inactive specific transcript) as a biomarker predicting BCL response to HDACi. We validated that low Xist expression predicts drug response in PDXs associated with a significant reduction of the breast CSC population.
  
  
  CONCLUSIONS
  Our study opens promising perspectives for the use of HDACi as a differentiation therapy targeting the breast CSCs and identified a biomarker to select patients with breast cancer susceptible to responding to this treatment.
authors.affiliation: Authors' Affiliations: Institut national de la santé et de la recherche medicale (INSERM), CRCM, U1068, Laboratoire d'Oncologie Moléculaire; Département de Biopathologie, Institut Paoli-Calmettes; Aix Marseille Université, F-13007; CNRS, CRCM, 7258; INSERM, CRCM, U1068, TrGET, Marseille; and Institut de Recherches Internationales Servier, Paris, France.
authors.forename: Marion A
authors.initials: MA
authors.lastname: Salvador
authors.forename: Julien
authors.initials: J
authors.lastname: Wicinski
authors.forename: Olivier
authors.initials: O
authors.lastname: Cabaud
authors.forename: Yves
authors.initials: Y
authors.lastname: Toiron
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Josselin
authors.forename: Hélène
authors.initials: H
authors.lastname: Lelièvre
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA; C512352:abexinostat