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Updated: Nov 15, 2025
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor
Dandan Song1, Huan He2, Indranil Sinha3
1Department of Biosciences and Nutrition, Karolinska Institutet, S-141 83 Huddinge, Sweden.
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.
Insights
Fra-1 protein overexpression in triple-negative breast cancer (TNBC) impacts olaparib treatment efficacy. Targeting Fra-1 may sensitize non-BRCA mutated TNBC to olaparib, improving patient outcomes.
Area of Science:
- Molecular Oncology
- Cancer Biology
- Pharmacology
Background:
- Fra-1, an AP-1 member, is overexpressed in triple-negative breast cancer (TNBC), contributing to tumor progression and treatment resistance.
- PARP1 (Poly(ADP-ribose) polymerase 1) interacts with Fra-1 and is targeted by olaparib, a drug used for BRCA-mutated TNBC.
Purpose of the Study:
- To investigate the functional impact of the Fra-1-PARP1 interaction on olaparib treatment efficacy in TNBC.
- To explore the potential of targeting Fra-1 as a therapeutic strategy for TNBC.
Main Methods:
- Protein-protein interaction analysis (Fra-1 and PARP1).
- Gene expression analysis of PARP1-regulated genes.
- In vitro studies assessing the effect of PARP1 inhibition/silencing and Fra-1 inhibition on TNBC cell lines.
- Clinical data analysis correlating PARP1 expression with patient outcomes.
Main Results:
- PARP1 downregulates Fra-1, reducing AP-1 transcriptional activity.
- Olaparib treatment or PARP1 silencing increases Fra-1 levels and activity, potentially leading to treatment resistance.
- Fra-1 inhibition sensitizes non-BRCA-mutated TNBC cells to olaparib.
- High PARP1 expression correlates with poor clinical outcome in breast cancer patients (excluding HER2-positive).
Conclusions:
- The Fra-1-PARP1 interaction modulates olaparib efficacy in TNBC.
- Targeting Fra-1 in combination with olaparib could enhance treatment outcomes for TNBC patients, particularly those with non-BRCA mutations.
