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Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer.

Kwon, Yeon-Jin, Petrie, Kevin, Leibovitch, Boris A, Zeng, Lei, Mezei, Mihaly, Howell, Louise, Gil, Veronica, Christova, Rossitza, Bansal, Nidhi, Yang, Shuai, Sharma, Rajal, Ariztia, Edgardo V, Frankum, Jessica, Brough, Rachel, Sbirkov, Yordan, Ashworth, Alan, Lord, Christopher J, Zelent, Arthur, Farias, Eduardo, Zhou, Ming-Ming and Waxman, Samuel (2015) Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. Molecular cancer therapeutics, 14 (8). pp. 1824-36. ISSN 1538-8514

Item Type: Article

Abstract

Triple-negative breast cancers (TNBC) lacking estrogen, progesterone, and HER2 receptors account for 10% to 20% of breast cancer and are indicative of poor prognosis. The development of effective treatment strategies therefore represents a pressing unmet clinical need. We previously identified a molecularly targeted approach to target aberrant epigenetics of TNBC using a peptide corresponding to the SIN3 interaction domain (SID) of MAD. SID peptide selectively blocked binding of SID-containing proteins to the paired α-helix (PAH2) domain of SIN3, resulting in epigenetic and transcriptional modulation of genes associated with epithelial-mesenchymal transition (EMT). To find small molecule inhibitor (SMI) mimetics of SID peptide, we performed an in silico screen for PAH2 domain-binding compounds. This led to the identification of the avermectin macrocyclic lactone derivatives selamectin and ivermectin (Mectizan) as candidate compounds. Both selamectin and ivermectin phenocopied the effects of SID peptide to block SIN3-PAH2 interaction with MAD, induce expression of CDH1 and ESR1, and restore tamoxifen sensitivity in MDA-MB-231 human and MMTV-Myc mouse TNBC cells in vitro. Treatment with selamectin or ivermectin led to transcriptional modulation of genes associated with EMT and maintenance of a cancer stem cell phenotype in TNBC cells. This resulted in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo. Underlining the potential of avermectins in TNBC, pathway analysis revealed that selamectin also modulated the expression of therapeutically targetable genes. Consistent with this, an unbiased drug screen in TNBC cells identified selamectin-induced sensitization to a number of drugs, including those targeting modulated genes.

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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 12440
Identification Number: https://doi.org/10.1158/1535-7163.MCT-14-0980-T
ISSN: 1538-8514
URI: http://sure.sunderland.ac.uk/id/eprint/12440
Official URL: https://mct.aacrjournals.org/content/14/8/1824.lon...

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 18 Aug 2020 18:51
Last Modified: 30 Sep 2020 10:48

Contributors

Author: Kevin Petrie ORCID iD
Author: Yeon-Jin Kwon
Author: Boris A Leibovitch
Author: Lei Zeng
Author: Mihaly Mezei
Author: Louise Howell
Author: Veronica Gil
Author: Rossitza Christova
Author: Nidhi Bansal
Author: Shuai Yang
Author: Rajal Sharma
Author: Edgardo V Ariztia
Author: Jessica Frankum
Author: Rachel Brough
Author: Yordan Sbirkov
Author: Alan Ashworth
Author: Christopher J Lord
Author: Arthur Zelent
Author: Eduardo Farias
Author: Ming-Ming Zhou
Author: Samuel Waxman

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences > Health Sciences

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