Abstract 4404: BRPF1 inhibition restores chemosensitivity in triple negative breast cancer via ribosomal pathway modulation

Abstract Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies, leaving chemotherapy as the primary treatment option. However, acquired resistance to drugs like paclitaxel (Taxol) poses a significant challenge, often driven by complex genetic and epigenetic changes. Our study identifies bromodomain and PHD finger-containing protein 1 (BRPF1) as a critical epigenetic regulator of Taxol resistance in TNBC cells, linking it to ribosome biogenesis and ABCB1-mediated drug resistance. We developed Taxol-resistant TNBC cell lines using an escalating dose protocol. These cells exhibited sustained resistance to high doses of Taxol, accompanied by significantly elevated expression of ABCB1. Epigenome-wide CRISPR/Cas9 screens revealed that BRPF1 is required for the survival of Taxol-resistant cells. Genetic depletion or pharmacological inhibition of BRPF1 using small-molecule inhibitors sensitized resistant cells to Taxol. RNA sequencing and functional assays demonstrated that BRPF1 loss led to the downregulation of ribosomal biogenesis and translation-related genes, impairing global protein synthesis. Notably, BRPF1 was found to directly bind the ABCB1 promoter, regulating the elevated ABCB1 levels. These findings highlight BRPF1’s dual role in maintaining translation machinery integrity and modulating ABCB1-driven chemoresistance. In conclusion, our work identifies BRPF1 as a novel therapeutic target for combating Taxol resistance in TNBC. Targeting BRPF1 disrupts ribosome biogenesis and reverses ABCB1-mediated drug resistance, offering a promising strategy to overcome chemotherapy failure in aggressive breast cancers. This work was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) 1003-216S461 and 1001-221S419. Citation Format: Ozlem Yedier Bayram, Ahmet Cingöz, Ebru Yilmaz, Ali Cenk Aksu, Beril Esin, Nareg Pinarbaşi-Degirmenci, Ayşe Derya Cavga, Beyza Dedeoglu, Buse Cevatemre, Hamzah Syed, MArtin Philpott, Adam P. Cribbs, Udo Opperman, Nathan A. Lack, Ceyda Açılan Ayhan, Tamer T. Onder, Tugba Bagci Onder. BRPF1 inhibition restores chemosensitivity in triple negative breast cancer via ribosomal pathway modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4404.