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