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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\n                    <jats:italic>BRCA1<\/jats:italic>\n                    functional status.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Olaparib 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\u2013TE chimeric transcripts harboring poison exons within tumorigenic genes and multi-exonic TE\u2013TE 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"738694v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.15.738694","type":"posted-content","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T13:35:17Z","timestamp":1784208917000},"source":"Crossref","is-referenced-by-count":0,"title":["Transposable elements shape olaparib response according to BRCA1 status in triple-negative breast cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9227-5583","authenticated-orcid":false,"given":"Daniela Moreira","family":"Mombach","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Gen\u00e9tica e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil"},{"name":"Hospital S\u00edrio-Liban\u00eas, S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8190-8568","authenticated-orcid":false,"given":"Carlos","family":"Mendez-Dorantes","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA"},{"name":"Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA"},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0223-3089","authenticated-orcid":false,"given":"Rafael L. V.","family":"Mercuri","sequence":"additional","affiliation":[{"name":"Hospital S\u00edrio-Liban\u00eas, S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9318-2725","authenticated-orcid":false,"given":"Phillip","family":"Schofield","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7172-0406","authenticated-orcid":false,"given":"Suelen Cristina","family":"Soares Baal","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica, Universidade Federal do Paran\u00e1, Curitiba, Paran\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4922-3427","authenticated-orcid":false,"given":"Maria Augusta","family":"Poersch","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica, Universidade Federal do Paran\u00e1, Curitiba, Paran\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1620-3761","authenticated-orcid":false,"given":"Kathleen H.","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA"},{"name":"Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA"},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5314-3107","authenticated-orcid":false,"given":"Jaqueline Carvalho","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica, Universidade Federal do Paran\u00e1, Curitiba, Paran\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elgion Lucio Silva","family":"Loreto","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica e Biologia Molecular, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4820-4155","authenticated-orcid":false,"given":"Pedro A. 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