LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer
Open Access
- 11 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Cancer
- Vol. 19 (1), 1-18
- https://doi.org/10.1186/s12943-020-01210-9
Abstract
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. 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. 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. TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.Keywords
Funding Information
- National Natural Science Foundation of China (81922048, 81902684, 81572583, 81874113, 81874112, 81502278, 81372848, 81370075, 81530075, 81773155, 81672600, and 8172203)
- Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (SHDC12010116)
- Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (2013ZYJB0302)
- Innovation Team of the Ministry of Education (IRT1223)
- Shanghai Key Laboratory of Breast Cancer (12DZ2260100)
- Training Plan of Excellent Talents in Shanghai Municipality Health System (2017YQ038)
- “Chen Guang” project, supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (17CG01)
- Shanghai Pujiang Program (18PJD007)
- Training Plan of Excellent Talents of FUSCC (YJYQ201602)
- Fok Ying-Tong Education Foundation for College Young Teachers (171034)
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