title: HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers.
abstract: BACKGROUND
  Inflammatory breast cancer (IBC) is the most lethal form of breast cancers with a 5-year survival rate of only 40 %. Despite its lethality, IBC remains poorly understood which has greatly limited its therapeutic management. We thus decided to utilize an integrative functional genomic strategy to identify the Achilles' heel of IBC cells.
  
  
  METHODS
  We have pioneered the development of genetic tools as well as experimental and analytical strategies to perform RNAi-based loss-of-function studies at a genome-wide level. Importantly, we and others have demonstrated that these functional screens are able to identify essential functions linked to certain cancer phenotypes. Thus, we decided to use this approach to identify IBC specific sensitivities.
  
  
  RESULTS
  We identified and validated HDAC6 as a functionally necessary gene to maintain IBC cell viability, while being non-essential for other breast cancer subtypes. Importantly, small molecule inhibitors for HDAC6 already exist and are in clinical trials for other tumor types. We thus demonstrated that Ricolinostat (ACY1215), a leading HDAC6 inhibitor, efficiently controls IBC cell proliferation both in vitro and in vivo. Critically, functional HDAC6 dependency is not associated with genomic alterations at its locus and thus represents a non-oncogene addiction. Despite HDAC6 not being overexpressed, we found that its activity is significantly higher in IBC compared to non-IBC cells, suggesting a possible rationale supporting the observed dependency.
  
  
  CONCLUSIONS
  Our finding that IBC cells are sensitive to HDAC6 inhibition provides a foundation to rapidly develop novel, efficient, and well-tolerated targeted therapy strategies for IBC patients.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Putcha
authors.affiliation: Department of Biomedical Informatics, Department of Systems Biology, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA.
authors.forename: Jiyang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodriguez-Barrueco
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Saucedo-Cuevas
authors.affiliation: Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Villagrasa
authors.affiliation: Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Murga-Penas
authors.affiliation: Acetylon Pharmaceuticals, Inc., 70 Fargo St, Suite 205, Boston, MA, 02210, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Quayle
authors.affiliation: Acetylon Pharmaceuticals, Inc., 70 Fargo St, Suite 205, Boston, MA, 02210, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Castro
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA.
authors.forename: David
authors.initials: D
authors.lastname: Llobet-Navas
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. alpaughm@mskcc.org.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Alpaugh
authors.affiliation: Department of Biomedical Informatics, Department of Systems Biology, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.|Department of Biochemistry and Molecular Biophysics, Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.|Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA. califano@c2b2.columbia.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA. jose.silva@mssm.edu.
authors.forename: Jose
authors.initials: J
authors.lastname: Silva
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D063990:Gene Ontology; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000201:enzymology* / Q000473:pathology
chemical_list: D056572:Histone Deacetylase Inhibitors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases