title: SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer.
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.
authors.affiliation: Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Burgess
authors.affiliation: Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia.|Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Bolderson
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Saunus
authors.affiliation: Northern Ireland Centre for Stratified Medicine, University of Ulster, Altnagelvin Hospital Campus, Londonderry, UK.|Center for Cancer Research and Cell Biology, Queen's University Belfast, United Kingdom.
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland, Australia.|QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Reid
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland, Australia.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: McNicol
authors.affiliation: The University of Queensland (UQ), UQ Centre for Clinical Research, Herston, Queensland, Australia.|Pathology Queensland, Royal Brisbane Women's Hospital, Herston, Queensland, Australia.|UQ School of Medicine, Herston, Queensland, Australia.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.
authors.forename: Katharine
authors.initials: K
authors.lastname: Cuff
authors.affiliation: UQ School of Medicine, Herston, Queensland, Australia.|Conjoint Endocrine Laboratory, Pathology Queensland, Queensland Health, Herston, Australia.
authors.forename: Kerry
authors.initials: K
authors.lastname: Richard
authors.affiliation: Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia.|Translational Cell Imaging Queensland, Translational Research Institute, Queensland, Australia.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Richard
authors.affiliation: Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia.|Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.|Translational Cell Imaging Queensland, Translational Research Institute, Queensland, Australia.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005029:Ethylenediamines / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D016016:Proportional Hazards Models; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D005029:Ethylenediamines; C474743:SASH1 protein, human; D025521:Tumor Suppressor Proteins; C004664:chloropyramine
keywords: SASH1; biomarker; breast cancer; chloropyramine