Abstract 4085: Blocking Fra-1 sensitises triple-negative breast cancer to olaparib

Abstract

Abstract Fra-1 (FOSL1), a member of the activator protein 1 (AP-1) transcription factor complex, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor progression and treatment resistance. We have previously identified 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells in a large screen, and this included PARP1 (Poly (ADP-ribose) polymerase 1). PARP1 inhibitor olaparib is currently in use for treatment of BRCA-mutated TNBC breast cancer. Here, we corroborate that PARP1 interacts with Fra-1, and we also find that PARP1 downregulates Fra-1 and reduces AP-1 transcriptional activity. Inhibition of PARP1, on the other hand, increases Fra-1 levels and enhances AP-1 transcriptional activity. Further, we find that upon inhibition of Fra-1, TNBC cells become sensitized to olaparib treatment. By comparing the Fra-1 and PARP1 regulated transcriptomes with Fra-1 chromatin binding site, we determine that a large fraction of PARP1-regulated genes is dependent on Fra-1. Finally, we show that PARP1 protein levels significantly correlate with Fra-1 in clinical breast cancer tumors, and we identify that while high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall, it is not in basal-like tumors. In conclusion, by exploring the functionality of the Fra-1 and PARP-1 interaction, we propose that targeting Fra-1 could serve as a therapeutic approach to improve olaparib treatment outcome for TNBC patients. Citation Format: Dandan Song, Huan He, Indranil Sinha, Linnea Pettersson, Feifei Yan, Lars-Arne Haldosen, Chunyan Zhao, Cecilia Williams. Blocking Fra-1 sensitises triple-negative breast cancer to olaparib [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4085.