Oncotarget

Research Papers:

SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer

Joshua T. Burgess, Emma Bolderson, Jodi M. Saunus, Shu-Dong Zhang, Lynne E. Reid, Anne Marie McNicol, Sunil R. Lakhani, Katharine Cuff, Kerry Richard, Derek J. Richard and Kenneth J. O’Byrne _

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Oncotarget. 2016; 7:72807-72818. https://doi.org/10.18632/oncotarget.12020

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Abstract

Joshua T. Burgess1, Emma Bolderson1,2, Jodi M. Saunus3,4, Shu-Dong Zhang5,6, Lynne E. Reid3,4, Anne Marie McNicol3, Sunil R. Lakhani3,7,8, Katharine Cuff2, Kerry Richard8,10, Derek J. Richard1,9, Kenneth J. O’Byrne1,2,9

1Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia

2Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia

3The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland, Australia

4QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

5Northern Ireland Centre for Stratified Medicine, University of Ulster, Altnagelvin Hospital Campus, Londonderry, UK

6Center for Cancer Research and Cell Biology, Queen’s University Belfast, United Kingdom

7Pathology Queensland, Royal Brisbane Women’s Hospital, Herston, Queensland, Australia

8UQ School of Medicine, Herston, Queensland, Australia

9Translational Cell Imaging Queensland, Translational Research Institute, Queensland, Australia

10Conjoint Endocrine Laboratory, Pathology Queensland, Queensland Health, Herston, Australia

Correspondence to:

Derek J. Richard, email: [email protected]

Kenneth J. O’Byrne, email: [email protected]

Keywords: SASH1, biomarker, breast cancer, chloropyramine

Received: March 29, 2016     Accepted: September 02, 2016     Published: September 14, 2016

ABSTRACT

Expression of the SASH1 protein is reduced in a range of human cancers and has been implicated in apoptotic cancer cell death. This study investigated whether increasing SASH1 expression could be a useful therapeutic strategy in breast cancer. Ectopic SASH1 expression increased apoptosis in 7/8 breast cancer cell lines. Subsequent in silico connectivity screening demonstrated that the clinically approved antihistamine drug, chloropyramine, increased SASH1 mRNA levels. Chloropyramine has previously been shown to have anti-tumour activity in breast cancer in part through modulation of FAK signalling, a pathway also regulated by SASH1. This study demonstrated that chloropyramine increased SASH1 protein levels in breast cancer cells. Consistent with this the agent reduced cell confluency in 7/8 cell lines treated irrespective of their ER status but not apoptosis incompetent MCF7 cells. In contrast SASH1 siRNA-transfected breast cancer cells exhibited reduced chloropyramine sensitivity. The prognostic significance of SASH1 expression was also investigated in two breast cancer cohorts. Expression was associated with favourable outcome in ER-positive cases, but only those of low histological grade/proliferative status. Conversely, we found a very strong inverse association in HER2+ disease irrespective of ER status, and in triple-negative, basal-like cases. Overall, the data suggest that SASH1 is prognostic in breast cancer and could have subtype-dependent effects on breast cancer progression. Pharmacologic induction of SASH1 by chloropyramine treatment of breast cancer warrants further preclinical and clinical investigation.


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