Priority Research Papers:
Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer
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Nidhi Bansal1, Kevin Petrie2, Rossitza Christova2,*, Chi-Yeh Chung3,*, Boris A. Leibovitch1, Louise Howell2, Veronica Gil2, Yordan Sbirkov2, EunJee Lee4, Joanna Wexler1, Edgardo V. Ariztia1, Rajal Sharma1, Jun Zhu4, Emily Bernstein5, Ming-Ming Zhou1, Arthur Zelent6, Eduardo Farias1 and Samuel Waxman1
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
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
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.
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