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

Burgess, Joshua T., Bolderson, Emma, Saunus, Jodi M., Zhang, Shu-Dong, Reid, Lynne E., McNicol, Anne Marie, Lakhani, Sunil R., Cuff, Katharine, Richard, Kerry, Richard, Derek J. and O'Byrne, Kenneth J. (2016) SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer. Oncotarget, 7 45: 72807-72818. doi:10.18632/oncotarget.12020


Author Burgess, Joshua T.
Bolderson, Emma
Saunus, Jodi M.
Zhang, Shu-Dong
Reid, Lynne E.
McNicol, Anne Marie
Lakhani, Sunil R.
Cuff, Katharine
Richard, Kerry
Richard, Derek J.
O'Byrne, Kenneth J.
Title SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer
Journal name Oncotarget   Check publisher's open access policy
ISSN 1949-2553
Publication date 2016-09-14
Sub-type Article (original research)
DOI 10.18632/oncotarget.12020
Open Access Status DOI
Volume 7
Issue 45
Start page 72807
End page 72818
Total pages 12
Place of publication Albany, NY, United States
Publisher Impact Journals LLC
Collection year 2017
Language eng
Formatted 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.
Keyword Biomarker
Breast cancer
Chloropyramine
SASH1
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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