Transposable elements shape olaparib response according to BRCA1 status in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. While PARP inhibitors, such as olaparib, show promise in BRCA1-deficient TNBC through synthetic lethality, up to 50% of patients fail to respond, highlighting the need to understand the molecular mechanisms underlying PARP inhibitors efficacy. Transposable elements (TEs), particularly LINE-1 elements, are increasingly recognized as modulators of genomic instability associated with DNA repair processes and potential key players in synthetic lethality. Here, we investigate the functional relationship between TE activity and olaparib treatment in TNBC with distinct BRCA1 functional status. MethodsWe performed comprehensive multi-OMICs analysis of four TNBC cell lines (two BRCA1-deficient: SUM1315 and MDA-MB-436; two BRCA1-proficient: MDA-MB-468 and BT549) treated with olaparib. We analyzed expression and differential expression of protein-coding genes, TEs, and gene-TE chimeric transcripts. Long-read whole-genome sequencing was employed to detect de novo TE insertions, complemented by a functional assay to quantify LINE-1 retrotransposition activity in olaparib-treated cells. ResultsOlaparib treatment induces extensive transcriptomic and genomic disorganization mediated by TEs, especially LINE-1, exclusively in BRCA1-deficient cells. We observed aberrant overexpression of both genes and TEs, including gene-TE chimeric transcripts harboring poison exons within tumorigenic genes and multi-exonic TE-TE chimeras capable of forming immunostimulatory double-stranded RNA (dsRNA) structures. Functional enrichment analyses revealed activation of antiviral immune pathways linked to LINE-1 activity. Consistently, orthogonal assays confirmed LINE-1 retrotransposition in BRCA1-deficient cells following olaparib exposure. ConclusionsOur findings demonstrate that olaparib treatment induces TE activation especially in BRCA1-deficient cells, a novel mechanism that may underlie synthetic lethality in TNBC. This TE activation triggers immune responses and genomic instability, providing new therapeutic opportunities through immunotherapy combinations and suggesting that TE activity may serve as a potential biomarker for treatment stratification of TNBC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/738694v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e8b202org.highwire.dtl.DTLVardef@fea1c5org.highwire.dtl.DTLVardef@12ea397org.highwire.dtl.DTLVardef@f60f1c_HPS_FORMAT_FIGEXP M_FIG C_FIG