Biology subjects

Loreto, E. L. S.

Publications and source records attributed to Loreto, E. L. S..

3 recordsLinked to original sources

bioRxiv2026

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@1cf6ecorg.highwire.dtl.DTLVardef@19725f7org.highwire.dtl.DTLVardef@3d9597org.highwire.dtl.DTLVardef@127f0bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A microvolume method for measuring catalase activity

We have developed and validated an innovative protocol for analyzing catalase activity in microvolumes using the NanoDrop spectrophotometer. This method offers a solution to the challenge of working with limited biological samples and provides an efficient alternative to conventional protocols that require larger sample volumes. Unlike typical microplate assays that aim to increase throughput or reduce costs, our protocol was developed specifically for scenarios where biological material is scarce, such as studies with small organisms like Panagrellus redivivus and Caenorhabditis elegans, as well as with certain tissues of Drosophila and other small organisms. A key advantage of the method described here is the ability to accurately measure catalase activity with as little as 2 L of sample, making it ideal for studies where sample availability is extremely limited. The results show that the protocol effectively assesses catalase efficiency and reflects the physiological and metabolic properties of the tissues studied. Inhibitors and denaturants were used to ensure specificity of catalase measurements and the method was optimized for minimal reagent consumption. This approach greatly expands the research possibilities on enzymatic activity in reduced biological models, especially in contexts where small samples are critical, such as limited tissue collections or small organisms Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/687299v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@9334fborg.highwire.dtl.DTLVardef@7b66baorg.highwire.dtl.DTLVardef@1957c28org.highwire.dtl.DTLVardef@10a44a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

TRANSPOSABLE ELEMENTS ALTER GENE EXPRESSION AND MAY IMPACT RESPONSE TO CISPLATIN THERAPY IN OVARIAN CANCER

Cisplatin is widely employed for cancer treatment; therefore, understanding resistance to this drug is critical for therapeutic practice. While studies have delved into differential gene expression in the context of cisplatin resistance, findings remain somewhat scant. In this study, we employed RNA-seq, ATAC-seq, and in-depth bioinformatics analyses to perform a detailed investigation of the cellular transcriptome, centering on Transposable Elements (TEs) expression in ovarian cancer cell lines both sensitive and resistant to cisplatin treatment. Our results reveal that cisplatin therapy alters the expression of protein-coding genes, but also key TEs, including LINE1, Alu, and endogenous retroviruses, in both cisplatin-sensitive and -resistant cell lines. By co-expressing with downstream genes or by creating chimeric transcripts with host genes at their insertion sites, these TEs seem to control the expression of protein-coding genes, including tumor-related genes. Notably, our model uncovers TEs influencing the expression of cancer genes and cancer pathways. Collectively, our findings indicate that TEs alterations associated with cisplatin treatment occur in critical cancer genes and cellular pathways synergically. In conclusion, this research highlights the importance of considering the entire spectrum of transcribed elements in the genome, especially TE expression, for a complete understanding of complex models like cancer response to treatment.

cancer biology↗