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Oncotarget. 2016 Nov 8;7(45):72807-72818. doi: 10.18632/oncotarget.12020.

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

Author information

1
Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia.
2
Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.
3
The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland, Australia.
4
QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
5
Northern Ireland Centre for Stratified Medicine, University of Ulster, Altnagelvin Hospital Campus, Londonderry, UK.
6
Center for Cancer Research and Cell Biology, Queen's University Belfast, United Kingdom.
7
Pathology Queensland, Royal Brisbane Women's Hospital, Herston, Queensland, Australia.
8
UQ School of Medicine, Herston, Queensland, Australia.
9
Conjoint Endocrine Laboratory, Pathology Queensland, Queensland Health, Herston, Australia.
10
Translational Cell Imaging Queensland, Translational Research Institute, Queensland, Australia.

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.

KEYWORDS:

SASH1; biomarker; breast cancer; chloropyramine

PMID:
27637080
PMCID:
PMC5341945
DOI:
10.18632/oncotarget.12020
[Indexed for MEDLINE]
Free PMC Article

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