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Oncotarget. 2017 Jul 5;8(46):80109-80123. doi: 10.18632/oncotarget.19019. eCollection 2017 Oct 6.

HDAC6 inhibitor WT161 downregulates growth factor receptors in breast cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
2
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
3
Department of Hematology, Chiba University Hospital, Chiba, Japan.
4
Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA, USA.
5
PerkinElmer Inc., Hopkinton, MA, USA.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA, USA.
7
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

Abstract

We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERα and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition. Moreover WT161 analog MAZ1793, which lacks HDAC inhibitory effect, similarly triggers cell line growth inhibition and downregulation of these receptors. We also confirm that WT161 significantly inhibits in vivo MCF7 cell growth, associated with downregulation of ERα, in a murine xenograft model. Finally, WT161 synergistically enhances bortezomib-induced cytotoxicity, even in bortezomib-resistant breast cancer cells. Our results therefore provide the rationale to develop a novel class of therapeutic agents targeting growth pathways central to the pathogenesis of breast cancer.

KEYWORDS:

breast cancer; epidermal growth factor receptor; estrogen receptor; histone deacetylase inhibitor; proteasome inhibitor

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