MUC1-C Integrates Chromatin Remodeling and PARP1 Activity in the DNA Damage Response of Triple-Negative Breast Cancer Cells

Cancer Res. 2019 Apr 15;79(8):2031-2041. doi: 10.1158/0008-5472.CAN-18-3259. Epub 2019 Mar 1.


The oncogenic MUC1-C protein is overexpressed in triple-negative breast cancer (TNBC) cells and contributes to their epigenetic reprogramming and chemoresistance. Here we show that targeting MUC1-C genetically or pharmacologically with the GO-203 inhibitor, which blocks MUC1-C nuclear localization, induced DNA double-strand breaks and potentiated cisplatin (CDDP)-induced DNA damage and death. MUC1-C regulated nuclear localization of the polycomb group proteins BMI1 and EZH2, which formed complexes with PARP1 during the DNA damage response. Targeting MUC1-C downregulated BMI1-induced H2A ubiquitylation, EZH2-driven H3K27 trimethylation, and activation of PARP1. As a result, treatment with GO-203 synergistically sensitized both mutant and wild-type BRCA1 TNBC cells to the PARP inhibitor olaparib. These findings uncover a role for MUC1-C in the regulation of PARP1 and identify a therapeutic strategy for enhancing the effectiveness of PARP inhibitors against TNBC. SIGNIFICANCE: These findings demonstrate that targeting MUC1-C disrupts epigenetics of the PARP1 complex, inhibits PARP1 activity, and is synergistic with olaparib in TNBC cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Chromatin Assembly and Disassembly / genetics*
  • DNA Damage*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Nude
  • Mucin-1 / genetics
  • Mucin-1 / metabolism*
  • Phthalazines / pharmacology*
  • Piperazines / pharmacology*
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • MUC1 protein, human
  • Mucin-1
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • olaparib