Abstract
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.
Funder
National Natural Science Foundation of China
Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals
Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System
Innovation Team of the Ministry of Education
Shanghai Key Laboratory of Breast Cancer
Training Plan of Excellent Talents in Shanghai Municipality Health System
“Chen Guang” project, supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation
Shanghai Pujiang Program
Training Plan of Excellent Talents of FUSCC
Fok Ying-Tong Education Foundation for College Young Teachers
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Cited by
59 articles.
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