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, Kenneth J. O’Byrne

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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.
Original languageEnglish
Pages (from-to)72807-72818
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 14 Sep 2016

Keywords

  • SASH1
  • biomarker
  • breast cancer
  • chloropyramine

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    Burgess, J. T., Bolderson, E., Saunus, J. M., Zhang, S-D., Reid, L. E., McNicol, A. M., Lakhani, S. R., Cuff, K., Richard, K., Richard, D. J., & O’Byrne, K. J. (2016). SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer. Oncotarget, 7(45), 72807-72818. https://doi.org/10.18632/oncotarget.12020