Related Experiment Video
Updated: May 28, 2025
Visualization of DNA Repair Proteins Interaction by Immunofluorescence
Published on: June 26, 2020
LINC01235 Promotes Clonal Evolution through DNA Replication Licensing-Induced Chromosomal Instability in Breast
Qi Zhang1,2, Xuliren Wang1,2, Zhibo Shao1,2
1Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Abstract:
Despite the development of HER2-targeting drugs such as trastuzumab and T-DXd, treatment resistance is a substantial challenge, often leading to relapse and distant metastasis. Tumor heterogeneity in HER2-positive breast cancer drives the evolution of resistant clones following therapeutic stress. However, the targetable drivers of anti-HER2 treatment resistance are not thoroughly identified. This study aims to use neoadjuvant-targeted therapy cohorts and a patient-derived organoid in vitro treatment model to uncover the potential targetable drivers of anti-HER2 treatment resistance. it is found that LINC01235 significantly enhances DNA replication licensing and chromosomal instability, fostering clonal expansion and evolution, and ultimately increasing resistance to therapeutic interventions. LINC01235 regulates global H3K27ac, H3K9ac, and H3K36me3 modifications, promotes H2A.Z expression in regulatory regions, and increases the accessibility of DNA licensing factors to their promoter regions. XRCC5 is identified as a key component for maintaining genomic stability, crucial for LINC01235's role in replication licensing. Furthermore, therapeutic strategies targeting LINC01235, including the use of antisense oligonucleotides or ATR inhibitors, which showed promise in overcoming treatment resistance are explored. These findings underscore the pivotal role of LINC01235 in driving resistance mechanisms and highlight novel avenues for targeted therapies to improve the outcomes of patients with HER2-positive breast cancer.
Insights
A novel long non-coding RNA, LINC01235, drives resistance to HER2-targeted therapies in breast cancer by promoting genomic instability. Targeting LINC01235 or ATR offers a promising strategy to overcome treatment resistance.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- HER2-positive breast cancer treatment resistance remains a significant clinical challenge, often driven by tumor heterogeneity and the evolution of resistant clones.
- Identifying targetable drivers of resistance to HER2-targeted therapies like trastuzumab and T-DXd is crucial for improving patient outcomes.
Purpose of the Study:
- To uncover potential targetable drivers of anti-HER2 treatment resistance in HER2-positive breast cancer.
- To investigate the role of LINC01235 in mediating resistance mechanisms and explore therapeutic strategies targeting it.
Main Methods:
- Utilized neoadjuvant-targeted therapy cohorts and a patient-derived organoid in vitro treatment model.
- Investigated the molecular mechanisms by which LINC01235 influences DNA replication, genomic stability, and gene expression.
- Explored therapeutic strategies targeting LINC01235 and associated pathways.
Main Results:
- LINC01235 was found to significantly enhance DNA replication licensing and chromosomal instability, promoting clonal expansion and resistance to HER2-targeted therapies.
- LINC01235 regulates global epigenetic modifications (H3K27ac, H3K9ac, H3K36me3), promotes H2A.Z expression, and increases DNA accessibility for licensing factors.
- XRCC5 was identified as a key component in LINC01235-mediated replication licensing and genomic stability.
- Therapeutic strategies targeting LINC01235 (e.g., antisense oligonucleotides) and ATR inhibitors showed promise in overcoming treatment resistance.
Conclusions:
- LINC01235 plays a pivotal role in driving resistance mechanisms in HER2-positive breast cancer.
- Targeting LINC01235 represents a novel therapeutic avenue to improve treatment efficacy and overcome resistance in HER2-positive breast cancer.
More Related Videos
05:55Author Spotlight: Unveiling the Role of SNF2L in Replication Fork Stability and Genome Duplication
Published on: August 23, 2024
08:15gDNA Enrichment by a Transposase-based Technology for NGS Analysis of the Whole Sequence of BRCA1, BRCA2, and 9 Genes Involved in DNA Damage Repair
Published on: October 6, 2014
Related Concept Videos
02:37Restarting Stalled Replication Forks
01:31The Intrinsic Apoptotic Pathway
02:37DNA Damage can Stall the Cell Cycle
01:27Molecular Factors Affecting Cell Division
Several proteins function as internal regulators to ensure each cell cycle stage is completed faithfully before proceeding to the next. Regulator molecules may act directly or influence the activity or production of other...
02:38S-Cdk Initiates DNA Replication
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...