LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer
Abstract Background Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their...
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doaj-f24e61bb66e348f5b2e76c28a3f516b42020-11-25T03:16:25ZengBMCMolecular Cancer1476-45982020-05-0119111810.1186/s12943-020-01210-9LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancerXi Jin0Li-Ping Ge1Da-Qiang Li2Zhi-Ming Shao3Gen-Hong Di4Xiao-En Xu5Yi-Zhou Jiang6Department of Breast Surgery, Fudan University Shanghai Cancer CenterDepartment of Breast Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityDepartment of Breast Surgery, Fudan University Shanghai Cancer CenterDepartment of Breast Surgery, Fudan University Shanghai Cancer CenterDepartment of Breast Surgery, Fudan University Shanghai Cancer CenterDepartment of Breast Surgery, Fudan University Shanghai Cancer CenterAbstract Background Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer. Methods The expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoid were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays. Results Herein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoid to the CDK4/6 inhibitor palbociclib both in vitro and in vivo. Conclusions TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.http://link.springer.com/article/10.1186/s12943-020-01210-9Breast cancerlncRNA TROJANCDK4/6 inhibitor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xi Jin Li-Ping Ge Da-Qiang Li Zhi-Ming Shao Gen-Hong Di Xiao-En Xu Yi-Zhou Jiang |
spellingShingle |
Xi Jin Li-Ping Ge Da-Qiang Li Zhi-Ming Shao Gen-Hong Di Xiao-En Xu Yi-Zhou Jiang LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer Molecular Cancer Breast cancer lncRNA TROJAN CDK4/6 inhibitor |
author_facet |
Xi Jin Li-Ping Ge Da-Qiang Li Zhi-Ming Shao Gen-Hong Di Xiao-En Xu Yi-Zhou Jiang |
author_sort |
Xi Jin |
title |
LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer |
title_short |
LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer |
title_full |
LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer |
title_fullStr |
LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer |
title_full_unstemmed |
LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer |
title_sort |
lncrna trojan promotes proliferation and resistance to cdk4/6 inhibitor via cdk2 transcriptional activation in er+ breast cancer |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2020-05-01 |
description |
Abstract Background Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer. Methods The expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoid were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays. Results Herein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoid to the CDK4/6 inhibitor palbociclib both in vitro and in vivo. Conclusions TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance. |
topic |
Breast cancer lncRNA TROJAN CDK4/6 inhibitor |
url |
http://link.springer.com/article/10.1186/s12943-020-01210-9 |
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