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.
Highlights
Breast cancer is the second most common cancer worldwide, comprising 25% of all female cancers
SAM and SH3 domain containing 1 (SASH1) has been described as a tumour suppressor, with overexpression resulting in an increase in cell death in lung cancer, melanoma, osteosarcoma and glioma cell lines [3, 6,7,8]
Consistent with this, we found that ectopic expression of SASH1 reduced breast cancer cell line viability, and so we hypothesised it could be involved in processes required for maintaining cancer cell viability in vivo, and that increasing its expression could be a novel treatment strategy
Summary
Breast cancer is the second most common cancer worldwide, comprising 25% of all female cancers. Expression of hormone (oestrogen (ER) and progesterone) and human epidermal growth factor 2 (HER2) receptors is routinely assessed in diagnostic practice, as these proteins are strongly prognostic and predict responsiveness to hormoneand HER2-targeted therapies, respectively. Owing to improved management strategies, the survival rate has increased in the past few decades, breast cancer is still the second highest cause of cancer-associated death in women [1]. For patients who experience distant relapse, secondary disease becomes increasingly harder to control with each line of therapy, with fewer treatment options due to efficient clonal adaptation by the tumour in response to new selection pressures. A key research priority is to identify new tumour cell sensitivities and drug targets, along with companion diagnostic markers to enable further personalisation of therapy, achieving maximal efficacy while minimising over-treatment. Deeper molecular and genetic understanding of breast tumourigenesis is intensifying the focus on drug repositioning as a means of capitalising on existing resources, and fast-tracking clinical development of ‘new’ treatments
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