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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.
LanguageEnglish
Pages72807-72818
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 14 Sep 2016

Fingerprint

Breast Neoplasms
Apoptosis
chloropyramine
Cell Line
Neoplasms
Histamine Antagonists
MCF-7 Cells
Computer Simulation
Small Interfering RNA
Proteins
Cell Death
Messenger RNA
Pharmaceutical Preparations

Keywords

  • SASH1
  • biomarker
  • breast cancer
  • chloropyramine

Cite this

Burgess, J. T., Bolderson, E., Saunus, J. M., Zhang, S-D., Reid, L. E., McNicol, A. M., ... 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
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. / SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer. In: Oncotarget. 2016 ; Vol. 7, No. 45. pp. 72807-72818.
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Burgess, JT, Bolderson, E, Saunus, JM, Zhang, S-D, Reid, LE, McNicol, AM, Lakhani, SR, Cuff, K, Richard, K, Richard, DJ & O’Byrne, KJ 2016, 'SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer', Oncotarget, vol. 7, no. 45, pp. 72807-72818. https://doi.org/10.18632/oncotarget.12020

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.; O’Byrne, Kenneth J.

In: Oncotarget, Vol. 7, No. 45, 14.09.2016, p. 72807-72818.

Research output: Contribution to journalArticle

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T1 - SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer

AU - Burgess, Joshua T.

AU - Bolderson, Emma

AU - Saunus, Jodi M.

AU - Zhang, Shu-Dong

AU - Reid, Lynne E.

AU - McNicol, Anne Marie

AU - Lakhani, Sunil R.

AU - Cuff, Katharine

AU - Richard, Kerry

AU - Richard, Derek J.

AU - O’Byrne, Kenneth J.

PY - 2016/9/14

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N2 - 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.

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