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Sunderland Repository records the research produced by the University of Sunderland including practice-based research and theses.

Abstract 4115: Inhibition of triple negative breast cancer cell invasion by the targeted interference of Sin3A function affecting Wnt and TGFβ signaling.

Kwon, Yeon-Jin, Leibovitch, Boris A., Bansal, Nidhi, Pereira, Lutecia, Ariztia, Edgardo V., Petrie, Kevin, Zelent, Arthur, Zhou, Ming-Ming, Farias, Eduardo F. and Waxman, Samuel (2016) Abstract 4115: Inhibition of triple negative breast cancer cell invasion by the targeted interference of Sin3A function affecting Wnt and TGFβ signaling. Cancer Research, 76 (14_Sup). p. 4115. ISSN 0008-5472

Item Type: Article


Cancer cell invasion is an obligatory step for metastatic dissemination that contributes to rapid relapse and a poor survival in TNBC patients. Development of novel therapeutic strategies to block tumor invasion is an unmet need for TNBC treatment and for other tumor types. We reported that decoys with the SID sequence designed to bind and inhibit the function of PAH-2 domain of Sin3A protein markedly prolong survival in the adjuvant setting due to inhibition of metastatic dissemination to the lungs and bone marrow in TNBC mouse models. Here, we show that TNBC cell lines treated with SID decoys (peptides) display a strong in vitro inhibition of migration and invasion. This is accompanied by actin cytoskeleton reorganization with increased cortical actin, and inhibition of proteolytic enzymes (MMP9; MT-MMP1 and uPA) involved in extracellular matrix degradation. DNA microarray and Ingenuity pathway analysis (IPA) showed that the SID decoys inhibit Wnt and TGFβ signaling that is associated with epithelial to mesenchymal transition (EMT). Treatment with SID decoy peptide downregulated WNT/β-catenin-driven transactivation as measured by decreased promoter H3K4me3 and decreased expression of Wnt target genes like LEF1 and TCF7L2. We also show that SID decoys induce translocation of nuclear β-catenin to the cytoplasm in TNBC at 24 hours. Wnt/β-catenin is critical for EMT, cancer stem cell self-renewal, and early invasion in TNBC. TGIF1, a transcription factor that modulates TGFβ and Wnt signaling pathways and known to to interact with the PAH2 domain of Sin3A, can be dissociated from Sin3A complex by SID decoy treatment as measured by co-immunoprecipitation (Co-IP) and proximity linked assay. DNA microarray of SID peptide treated TNBC cells shows inhibition of TGFβ signaling evidenced by downregulation of MMP9, MT1-MMP and PLAU, known target genes of this pathway. This is in line with inhibition of the EMT program predicted by the IPA analysis in SID peptide treated TNBC. Taken together, the results indicate that SID decoys have potential value as therapeutic agents to revert the EMT program in TNBC that should translate into the inhibition of metastasis dissemination and eradication of residual disease in TNBC. To test this in clinic future investigations will involve the use of our previously identified small molecule mimetic of SID peptide, selamectin that is also a FDA approved drug. Use of a recently constructed cyclic stapled peptide that inhibits PAH-2 binding and invasion at <10nM is also anticipated.

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Depositing User: Kevin Petrie


Item ID: 15807
Identification Number:
ISSN: 0008-5472
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Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD

Catalogue record

Date Deposited: 22 Mar 2023 13:35
Last Modified: 22 Mar 2023 13:35


Author: Kevin Petrie ORCID iD
Author: Yeon-Jin Kwon
Author: Boris A. Leibovitch
Author: Nidhi Bansal
Author: Lutecia Pereira
Author: Edgardo V. Ariztia
Author: Arthur Zelent
Author: Ming-Ming Zhou
Author: Eduardo F. Farias
Author: Samuel Waxman

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine


Sciences > Biomedical Sciences

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