Targeting the SIN3A-PF1 protein interaction in triple negative breast cancer blocks epithelial-to-mesenchymal transition

Targeting the SIN3A-PF1 protein interaction in triple negative breast cancer blocks epithelial-to-mesenchymal transition

Bansal et al. (2025) showed that targeting the SIN3A-PF1 protein interaction blocks epithelial-to-mesenchymal transition (EMT), suppresses cancer stem cell properties, and reduces tumor growth and metastasis in triple-negative breast cancer (TNBC) by Tat-SID-mediated disruption of the interaction between PAH2 and SID-containing MAD.

Breast cancer is a complex disease with diverse molecular and clinical phenotypes, and the basis for molecular subtyping of this cancer type relies on the status of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (Her2). Since triple-negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options, Bansal et al. (2015) investigated the functional consequences of selectively blocking the paired amphipathic α-helix (PAH2) domain of SIN3.

Aberrant epigenetics in this subtype represents a potential therapeutic opportunity; however, a better understanding of the mechanisms contributing to TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation. The SIN3 molecular scaffold is critical in multiple cellular processes, including epigenetic regulation.

Bansal et al. focused their investigation on the plant homeodomain (PHD)-containing protein PF1 (PHF12), which links SIN3 PAH2 to a chromatin-modifying protein complex containing MRG15, LID (the Drosophila homolog of KDM5A/B) and EMSY that has been implicated in breast cancer, identifying the SID-containing adaptor PF1 as required to maintain the TNBC stem cell phenotype and epithelial-to-mesenchymal transition (EMT). 

The study used a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID) to investigate the effects of selectively blocking SIN3's paired amphipathic α-helix (PAH2) domain. The Tat-SID peptide blocked the interaction between SIN3A and PF1, resulting in epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers, leading to reduced primary tumor growth and disseminated metastatic disease in vivo. Additionally, PF1 knockdown showed similar results in vitro and in vivo, demonstrating a critical role for the SIN3A-PF1 complex in TNBC and providing a rationale for its therapeutic targeting.

Bansal et al. (2015) dissected the function of SIN3 PAH2 by using a 31-mer decoy peptide comprising amino acids 5 to 24 of MAD SID and the nuclear localization signal of HIV-1 Tat (Tat-SID).

        Peptides utilized in the study

Synthetic Tat-Sid was used with or without FITC conjugation. All peptides were used at a purity level of 95% as assessed by analytical reversed phase-high-performance liquid chromatography (BioSynthesis, Inc).

References

Abramson VG and Mayer IA. Molecular Heterogeneity of Triple Negative Breast Cancer. Curr Breast Cancer Rep. 2014; 6:154-158. [PMC]

Ayer DE, Eisenman RN. A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation. Genes Dev. 1993 Nov;7(11):2110-9. [Genes & Development]

Bansal N, Petrie K, Christova R, Chung CY, Leibovitch BA, Howell L, Gil V, Sbirkov Y, Lee E, Wexler J, Ariztia EV, Sharma R, Zhu J, Bernstein E, Zhou MM, Zelent A, Farias E, Waxman S. Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer. Oncotarget. 2015 Oct 27;6(33):34087-105. [PMC]

Kadamb R, Leibovitch BA, Farias EF, Dahiya N, Suryawanshi H, Bansal N, Waxman S. Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A-PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1. Transl Oncol. 2022 Feb;16:101320. [PMC]

Mad-Max complex

MXD1

SIN3A

Sommer A, Hilfenhaus S, Menkel A, Kremmer E, Seiser C, Loidl P, Lüscher B. Cell growth inhibition by the Mad/Max complex through recruitment of histone deacetylase activity. Curr Biol. 1997 Jun 1;7(6):357-65. [Current Biology]

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