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 and Waxman, Samuel (2015) Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer. Oncotarget, 6 (33). pp. 34087-105. ISSN 1949-2553
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2015 Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer.pdf - Published Version
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Abstract
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.
| Item Type: | Article |
|---|---|
| Depositing User: | Kevin Petrie |
| URI: | https://sure.sunderland.ac.uk/id/eprint/12442 |
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