Targeting triple negative breast cancer with histone deacetylase inhibitors

ABSTRACT

Introduction: Triple negative breast cancer (TNBC) is a heterogeneous disease characterized by poor outcomes, higher rates of relapse, lack of biomarkers for rational use of targeted treatments and insensitivity to current available treatments. Histone deacetylase inhibitors (HDACis) perform multiple cytotoxic actions and are emerging as promising multifunctional agents in TNBC.

Areas covered: This review focuses on the challenges so far addressed in the targeted treatment of TNBC and explores the various mechanisms by which HDACis control cancer cell growth, tumor progression and metastases. Pivotal preclinical trials on HDACis like panobinostat, vorinostat, and entinostat show that these epigenetic agents exert an anti-proliferative effect on TNBC cells and control tumor growth by multiple mechanisms of action, including apoptosis and regulation of the epithelial to mesenchimal transition (EMT). Combination studies have reported the synergism of HDACis with other anticancer agents.

Expert opinion: In recent years, treatment of TNBC has recorded a high number of failures in the development of targeted agents. HDACis alone or in combination strategies show promising activity in TNBC and could have implications for the future targeted treatment of TNBC patients. Future research should identify which agent synergizes better with HDACis and which patient will benefit more from these epigenetic agents.

KEYWORDS:

• Epigenetic agents
• histone deacetylase inhibitors
• triple negative breast cancer
• targeted therapies

Article highlights

• Triple negative breast cancer is a heterogeneous disease with aggressive behavior and poor prognosis

• In recent years several targeted treatment options have been explored for TNBC with disappointing results

• Histone deacetylation is an important regulator of gene expression in physiological and pathological systems

• Histone deacetylase inhibitors exert multiple effects on TNBC: chromatin remodeling, DNA damaging, apoptosis induction, cancer stem cells inhibition, regulation of the epithelial to mesenchimal transition, antiangiogenic effect, functional activation of ERα, immunomodulatory activity.

• Panobinostat, entinostat, vorinostat are first in class HDACis in TNBC preclinical models in vitro and in vivo and are currently under investigation as potential therapeutics for targeting triple negative breast cancer patients.

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Acknowledgments

I would like thank Ms. Antonio Guadalupi for his support in the linguistic revision of the text.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper received no funding