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Breast Cancer Research
Published in: Breast Cancer Research 1/2015

Open Access 01-12-2015 | Research article

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

Authors: Preeti Putcha, Jiyang Yu, Ruth Rodriguez-Barrueco, Laura Saucedo-Cuevas, Patricia Villagrasa, Eva Murga-Penas, Steven N. Quayle, Min Yang, Veronica Castro, David Llobet-Navas, Daniel Birnbaum, Pascal Finetti, Wendy A. Woodward, François Bertucci, Mary L. Alpaugh, Andrea Califano, Jose Silva

Published in: Breast Cancer Research | Issue 1/2015

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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.
Appendix
Available only for authorised users
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Metadata
Title
HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers
Authors
Preeti Putcha
Jiyang Yu
Ruth Rodriguez-Barrueco
Laura Saucedo-Cuevas
Patricia Villagrasa
Eva Murga-Penas
Steven N. Quayle
Min Yang
Veronica Castro
David Llobet-Navas
Daniel Birnbaum
Pascal Finetti
Wendy A. Woodward
François Bertucci
Mary L. Alpaugh
Andrea Califano
Jose Silva
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2015
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-015-0658-0

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