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// Nidhi Bansal 1 , Kevin Petrie 2 , Rossitza Christova 2,* , Chi-Yeh Chung 3,* , Boris A. Leibovitch 1 , Louise Howell 2 , Veronica Gil 2 , Yordan Sbirkov 2 , EunJee Lee 4 , Joanna Wexler 1 , Edgardo V. Ariztia 1 , Rajal Sharma 1 , Jun Zhu 4 , Emily Bernstein 5 , Ming-Ming Zhou 1 , Arthur Zelent 6 , Eduardo Farias 1 and Samuel Waxman 1 1 Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA 2 Division of Clinical Studies, Institute of Cancer Research, Sutton, United Kingdom 3 Department of Oncological Sciences, Department of Genetics and Genomic Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA 4 Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, USA 5 Department of Oncological Sciences, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA 6 Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Florida, USA * These authors have contributed equally to this work Correspondence to: Samuel Waxman, email: // Keywords : epigenetics, SIN3, PF1, triple negative breast cancer, cancer stem cells Received : July 17, 2015 Accepted : September 24, 2015 Published : October 09, 2015 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.