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

  • Oncotarget. 2016 Nov 8;7(45):72807-72818. doi: 10.18632/oncotarget.12020.
Joshua T Burgess  1 ,  Emma Bolderson  1  2 ,  Jodi M Saunus  3  4 ,  Shu-Dong Zhang  5  6 ,  Lynne E Reid  3  4 ,  Anne Marie McNicol  3 ,  Sunil R Lakhani  3  7  8 ,  Katharine Cuff  2 ,  Kerry Richard  8  9 ,  Derek J Richard  1  10 ,  Kenneth J O'Byrne  1  2  10
Affiliations
  • 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.
PMID: 27637080 DOI: 10.18632/oncotarget.12020
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.
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