Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor
| Autor: | Huan He, Cecilia Williams, Dandan Song, Lars Arne Haldosén, Feifei Yan, Amena Archer, Indranil Sinha, Chunyan Zhao, Linnea Hases |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Poly (ADP-Ribose) Polymerase-1 Triple Negative Breast Neoplasms Poly(ADP-ribose) Polymerase Inhibitors B7-H1 Antigen Piperazines Olaparib 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer PARP1 Cell Line Tumor Humans Gene silencing Medicine Adverse effect Triple-negative breast cancer business.industry medicine.disease Gene Expression Regulation Neoplastic Transcription Factor AP-1 030104 developmental biology Oncology chemistry Tumor progression 030220 oncology & carcinogenesis PARP inhibitor Cancer research Phthalazines Female business Proto-Oncogene Proteins c-fos |
| Zdroj: | Cancer Letters. 506:23-34 |
| ISSN: | 0304-3835 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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