Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer

• Published in: Oncotarget Vol. 6; no. 33; pp. 34087 - 34105
• Main Authors: Bansal, Nidhi, Petrie, Kevin, Christova, Rossitza, Chung, Chi-Yeh, Leibovitch, Boris A, Howell, Louise, Gil, Veronica, Sbirkov, Yordan, Lee, EunJee, Wexler, Joanna, Ariztia, Edgardo V, Sharma, Rajal, Zhu, Jun, Bernstein, Emily, Zhou, Ming-Ming, Zelent, Arthur, Farias, Eduardo, Waxman, Samuel
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 27.10.2015
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Epithelial-Mesenchymal Transition - physiology; Female; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Mice; Neoplastic Stem Cells - pathology; Priority Research Paper; Protein Structure, Tertiary; Repressor Proteins - metabolism; Spheroids, Cellular; Transcription Factors - genetics; Transcription Factors - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Cells, Cultured; PF1; triple negative breast cancer; cancer stem cells; SIN3; epigenetics
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6048

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.