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

Citation

Bansal N, Petrie K, Christova R, Chung C, Leibovitch B, Howell L, Gil V, Sbirkov Y, Lee E, Wexler J, Ariztia EV, Sharma R, Zhu J, Bernstein E, Zhou M, Zelent A, Farias EF & Waxman S (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. 34087-34105. https://doi.org/10.18632/oncotarget.6048

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 diseasein vivo. In support of these findings, knockdown ofPF1expression phenocopied treatment with Tat-SID bothin vitroandin vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.

Keywords
epigenetics; SIN3; PF1; triple negative breast cancer; cancer stem cells

Journal
Oncotarget: Volume 6, Issue 33