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.

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.

MeSH terms

  • Adult
  • Aged
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Biomarkers, Tumor
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Ethylenediamines / pharmacology*
  • Female
  • Gene Expression
  • Humans
  • Middle Aged
  • Neoplasm Grading
  • Prognosis
  • Proportional Hazards Models
  • Tumor Burden
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Biomarkers, Tumor
  • Ethylenediamines
  • SASH1 protein, human
  • Tumor Suppressor Proteins
  • chloropyramine