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SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer.
- Source :
-
Oncotarget [Oncotarget] 2016 Nov 08; Vol. 7 (45), pp. 72807-72818. - Publication Year :
- 2016
-
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.
- Subjects :
- Adult
Aged
Apoptosis drug effects
Apoptosis genetics
Biomarkers, Tumor
Breast Neoplasms pathology
Cell Line, Tumor
Female
Gene Expression
Humans
Middle Aged
Neoplasm Grading
Prognosis
Proportional Hazards Models
Tumor Burden
Tumor Suppressor Proteins metabolism
Breast Neoplasms genetics
Breast Neoplasms mortality
Drug Resistance, Neoplasm genetics
Ethylenediamines pharmacology
Tumor Suppressor Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 45
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27637080
- Full Text :
- https://doi.org/10.18632/oncotarget.12020