title: Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer.
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.
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Yeon-Jin
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Leibovitch
authors.affiliation: Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Mihaly
authors.initials: M
authors.lastname: Mezei
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Howell
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Veronica
authors.initials: V
authors.lastname: Gil
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rossitza
authors.initials: R
authors.lastname: Christova
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Bansal
authors.affiliation: Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yang
authors.affiliation: Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Rajal
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Edgardo V
authors.initials: EV
authors.lastname: Ariztia
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frankum
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brough
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Yordan
authors.initials: Y
authors.lastname: Sbirkov
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: The Institute of Cancer Research, London, United Kingdom. Division of Hemato-Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Farias
authors.affiliation: Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Samuel.waxman@mssm.edu.
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000977:Antiparasitic Agents / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D054730:Protein Interaction Domains and Motifs; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000977:Antiparasitic Agents; C513384:CDH1 protein, human; D015820:Cadherins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012097:Repressor Proteins; D007559:Ivermectin; C019264:avermectin; C414354:selamectin