LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast Cancer
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-04-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202413527 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849729682734317568 |
|---|---|
| author | Qi Zhang Xuliren Wang Zhibo Shao Yi Zhang Liyi Zhang Ming Chen Xujie Zhou Han Zhu Yue Zhou Xinya Lu Pei Li Weiru Chi Lun Li Zhi‐Ming Shao Shenglin Huang Jingyan Xue Yayun Chi Jiong Wu Bingqiu Xiu |
| author_facet | Qi Zhang Xuliren Wang Zhibo Shao Yi Zhang Liyi Zhang Ming Chen Xujie Zhou Han Zhu Yue Zhou Xinya Lu Pei Li Weiru Chi Lun Li Zhi‐Ming Shao Shenglin Huang Jingyan Xue Yayun Chi Jiong Wu Bingqiu Xiu |
| author_sort | Qi Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-436e5de9a15442e5bd6b4dd7984efc5f |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-436e5de9a15442e5bd6b4dd7984efc5f2025-08-20T03:09:08ZengWileyAdvanced Science2198-38442025-04-011214n/an/a10.1002/advs.202413527LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast CancerQi Zhang0Xuliren Wang1Zhibo Shao2Yi Zhang3Liyi Zhang4Ming Chen5Xujie Zhou6Han Zhu7Yue Zhou8Xinya Lu9Pei Li10Weiru Chi11Lun Li12Zhi‐Ming Shao13Shenglin Huang14Jingyan Xue15Yayun Chi16Jiong Wu17Bingqiu Xiu18Department of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaFudan University Shanghai Cancer Center Key Laboratory of Medical Epigenetics and Metabolism Institutes of Biomedical Sciences Fudan University Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaDepartment of Breast Surgery Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Shanghai 200032 ChinaAbstract 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.https://doi.org/10.1002/advs.202413527ATR inhibitorschromosomal instabilitiesDNA replication licensingHER2‐positive breast cancersLINC01235 |
| spellingShingle | Qi Zhang Xuliren Wang Zhibo Shao Yi Zhang Liyi Zhang Ming Chen Xujie Zhou Han Zhu Yue Zhou Xinya Lu Pei Li Weiru Chi Lun Li Zhi‐Ming Shao Shenglin Huang Jingyan Xue Yayun Chi Jiong Wu Bingqiu Xiu LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast Cancer Advanced Science ATR inhibitors chromosomal instabilities DNA replication licensing HER2‐positive breast cancers LINC01235 |
| title | LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast Cancer |
| title_full | LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast Cancer |
| title_fullStr | LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast Cancer |
| title_full_unstemmed | LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast Cancer |
| title_short | LINC01235 Promotes Clonal Evolution through DNA Replication Licensing‐Induced Chromosomal Instability in Breast Cancer |
| title_sort | linc01235 promotes clonal evolution through dna replication licensing induced chromosomal instability in breast cancer |
| topic | ATR inhibitors chromosomal instabilities DNA replication licensing HER2‐positive breast cancers LINC01235 |
| url | https://doi.org/10.1002/advs.202413527 |
| work_keys_str_mv | AT qizhang linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT xulirenwang linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT zhiboshao linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT yizhang linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT liyizhang linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT mingchen linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT xujiezhou linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT hanzhu linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT yuezhou linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT xinyalu linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT peili linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT weiruchi linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT lunli linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT zhimingshao linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT shenglinhuang linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT jingyanxue linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT yayunchi linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT jiongwu linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer AT bingqiuxiu linc01235promotesclonalevolutionthroughdnareplicationlicensinginducedchromosomalinstabilityinbreastcancer |