Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple-negative breast cancer

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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1824-1836
Number of pages13
JournalMolecular Cancer Therapeutics
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2015

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Triple Negative Breast Neoplasms
Co-Repressor Proteins
Ivermectin
Epithelial-Mesenchymal Transition
Epigenomics
Therapeutics
Protein Interaction Domains and Motifs
Genes
Gene Targeting
Neoplastic Stem Cells
Lactones
Progesterone Receptors
Tamoxifen
Pharmaceutical Preparations
Computer Simulation
avermectin
Estrogens
Maintenance
selamectin
Breast Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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 Z; Farias, Eduardo; Zhou, Ming Ming; Waxman, Samuel.

In: Molecular Cancer Therapeutics, Vol. 14, No. 8, 01.08.2015, p. 1824-1836.

Research output: Contribution to journalArticle

Kwon, YJ, Petrie, K, Leibovitch, BA, Zeng, L, Mezei, M, Howell, L, Gil, V, Christova, R, Bansal, N, Yang, S, Sharma, R, Ariztia, EV, Frankum, J, Brough, R, Sbirkov, Y, Ashworth, A, Lord, CJ, Zelent, AZ, Farias, E, Zhou, MM & Waxman, S 2015, 'Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple-negative breast cancer', Molecular Cancer Therapeutics, vol. 14, no. 8, pp. 1824-1836. https://doi.org/10.1158/1535-7163.MCT-14-0980-T
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 Z ; Farias, Eduardo ; Zhou, Ming Ming ; Waxman, Samuel. / Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple-negative breast cancer. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 8. pp. 1824-1836.
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AU - Mezei, Mihaly

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AU - Gil, Veronica

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