title: Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer.
abstract: Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic α-helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial-to-mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment also led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Bansal
authors.affiliation: Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrie
authors.affiliation: Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Rossitza
authors.initials: R
authors.lastname: Christova
authors.affiliation: Department of Oncological Sciences, Department of Genetics and Genomic Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Chi-Yeh
authors.initials: CY
authors.lastname: Chung
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Leibovitch
authors.affiliation: Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Howell
authors.affiliation: Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Veronica
authors.initials: V
authors.lastname: Gil
authors.affiliation: Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Yordan
authors.initials: Y
authors.lastname: Sbirkov
authors.affiliation: Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: EunJee
authors.initials: E
authors.lastname: Lee
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wexler
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Edgardo V
authors.initials: EV
authors.lastname: Ariztia
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Rajal
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Oncological Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Bernstein
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.affiliation: Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Farias
authors.affiliation: Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D018874:Spheroids, Cellular; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; C430869:PHF12 protein, human; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D014157:Transcription Factors; D056264:Sin3 Histone Deacetylase and Corepressor Complex
keywords: PF1; SIN3; cancer stem cells; epigenetics; triple negative breast cancer