Priority Research Papers:

This article has been corrected. Correction in: Oncotarget. 2021; 12:1736-1736.

HDAC6 inhibitor WT161 downregulates growth factor receptors in breast cancer

Teru Hideshima, Ralph Mazitschek, Jun Qi, Naoya Mimura, Jen-Chieh Tseng, Andrew L. Kung, James E. Bradner and Kenneth C. Anderson _

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Oncotarget. 2017; 8:80109-80123. https://doi.org/10.18632/oncotarget.19019

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Teru Hideshima1, Ralph Mazitschek2, Jun Qi1, Naoya Mimura1,5, Jen-Chieh Tseng3,6, Andrew L. Kung3,4,7, James E. Bradner1,8 and Kenneth C. Anderson1

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 Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA, USA

4 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital Boston, Boston, MA, USA

5 Department of Hematology, Chiba University Hospital, Chiba, Japan

6 PerkinElmer Inc., Hopkinton, MA, USA

7 Memorial Sloan Kettering Cancer Center, New York, NY, USA

8 Novartis Institutes for BioMedical Research, Cambridge, MA, USA

Correspondence to:

Kenneth C. Anderson, email:

Keywords: histone deacetylase inhibitor, breast cancer, estrogen receptor, epidermal growth factor receptor, proteasome inhibitor

Received: March 24, 2017 Accepted: June 08, 2017 Published: July 05, 2017


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.

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