Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor

  • Cancer Lett. 2021 May 28:506:23-34. doi: 10.1016/j.canlet.2021.02.018.
Dandan Song  1 ,  Huan He  2 ,  Indranil Sinha  3 ,  Linnea Hases  4 ,  Feifei Yan  5 ,  Amena Archer  6 ,  Lars-Arne Haldosen  7 ,  Chunyan Zhao  8 ,  Cecilia Williams  9
Affiliations
  • 1. Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83 Huddinge, Sweden. Electronic address: [email protected].
  • 2. School of Public Health, Jilin University, Changchun, 130021, China. Electronic address: [email protected].
  • 3. Department of Women's and Children's Health, Karolinska Institutet, S-171 77 Stockholm, Sweden. Electronic address: [email protected].
  • 4. Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83 Huddinge, Sweden; Science for Life Laboratory, Department of Protein Science, CBH, KTH Royal Institute of Technology, Solna, Sweden. Electronic address: [email protected].
  • 5. Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83 Huddinge, Sweden. Electronic address: [email protected].
  • 6. Science for Life Laboratory, Department of Protein Science, CBH, KTH Royal Institute of Technology, Solna, Sweden. Electronic address: [email protected].
  • 7. Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83 Huddinge, Sweden. Electronic address: [email protected].
  • 8. Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83 Huddinge, Sweden. Electronic address: [email protected].
  • 9. Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83 Huddinge, Sweden; Science for Life Laboratory, Department of Protein Science, CBH, KTH Royal Institute of Technology, Solna, Sweden. Electronic address: [email protected].
PMID: 33652085 DOI: 10.1016/j.canlet.2021.02.018
Abstract

The AP-1 member Fra-1 is overexpressed in TNBC and plays crucial roles in tumor progression and treatment resistance. In a previous large-scale screen, we identified PARP1 to be among 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells. PARP1 Inhibitor (olaparib) is currently in clinical use for treatment of BRCA-mutated TNBC breast Cancer. Here, we demonstrate that the Fra-1-PARP1 interaction impacts the efficacy of olaparib treatment. We show that PARP1 interacts with and downregulates Fra-1, thereby reducing AP-1 transcriptional activity. Olaparib treatment, or silencing of PARP1, consequently, increases Fra-1 levels and enhances its transcriptional activity. Increased Fra-1 can have adverse effect, including treatment resistance. We also found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We show that by inhibiting Fra-1/AP-1, non-BRCA-mutated TNBC cells can become sensitized to olaparib treatment. We identify that high PARP1 expression is indicative of a poor clinical outcome in breast Cancer patients overall (P = 0.01), but not for HER-2 positive patients. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a combinatory therapeutic approach to improve olaparib treatment outcome for TNBC patients.

Keywords
AP-1; Fra-1; Olaparib; PARP1; Triple-negative breast cancer.
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