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Breast Cancer Res. 2015 Dec 8;17(1):149. doi: 10.1186/s13058-015-0658-0.

HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers.

Author information

1
Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA.
2
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.
3
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA.
4
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5
Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
6
Acetylon Pharmaceuticals, Inc., 70 Fargo St, Suite 205, Boston, MA, 02210, USA.
7
Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.
8
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. alpaughm@mskcc.org.
9
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.
10
Department of Biochemistry and Molecular Biophysics, Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.
11
Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA. califano@c2b2.columbia.edu.
12
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-6574, USA. jose.silva@mssm.edu.

Abstract

INTRODUCTION:

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.

CONCLUSION:

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.

PMID:
26643555
PMCID:
PMC4672555
DOI:
10.1186/s13058-015-0658-0
[Indexed for MEDLINE]
Free PMC Article

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