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

Nidhi Bansal, Kevin Petrie, Rossitza Christova, Chi Yeh Chung, Boris A. Leibovitch, Louise Howell, Veronica Gil, Yordan Sbirkov, Eun Jee Lee, Joanna Wexler, Edgardo V. Ariztia, Rajal Sharma, Jun Zhu, Emily Bernstein, Ming Ming Zhou, Arthur Zelent, Eduardo Farias, Samuel Waxman

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 a-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.

Original languageEnglish (US)
Pages (from-to)34087-34105
Number of pages19
JournalOncotarget
Volume6
Issue number33
DOIs
StatePublished - 2015

Keywords

  • Cancer stem cells
  • Epigenetics
  • PF1
  • SIN3
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Oncology

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