Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor. (28th May 2021)

• Record Type: Journal Article
• Authors: Song, Dandan; He, Huan; Sinha, Indranil; Hases, Linnea; Yan, Feifei; Archer, Amena; Haldosen, Lars-Arne; Zhao, Chunyan; Williams, Cecilia
• Is Part Of: Cancer letters. Volume 506(2021)
• Page Start: 23
• Page End: 34
• Publication Date: 2021-05-28
• Subjects: Fra-1 -- PARP1 -- AP-1 -- Olaparib -- Triple-negative breast cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.02.018
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: PARP1 interacts and PARylates Fra-1, reducing Fra-1 expression and activity. Preclinical demonstration of combining Fra-1/AP-1 inhibitor with olaparib for increased efficacy. Genome-wide transcriptional effect of olaparib and AP-1 knockdown are provided. PARP1 has a prognostic biomarker potential.