LncRNA TROJAN promotes proliferation and resistance to CDK4/6 inhibitor via CDK2 transcriptional activation in ER+ breast cancer

• Published in: Molecular cancer Vol. 19; no. 1; p. 87
• Main Authors: Jin, Xi, Ge, Li-Ping, Li, Da-Qiang, Shao, Zhi-Ming, Di, Gen-Hong, Xu, Xiao-En, Jiang, Yi-Zhou
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.05.2020; BioMed Central; BMC
• Subjects: Animals; Antibodies; Antisense oligonucleotides; Antisense RNA; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer research; CDK4/6 inhibitor; Cell cycle; Cell growth; Cell Proliferation; Chromatin; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-dependent kinases; DNA microarrays; Drug resistance; Drug Resistance, Neoplasm; Estrogen receptors; Female; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Humans; Immunoprecipitation; Kinases; lncRNA TROJAN; Mass spectrometry; Mass spectroscopy; Mice; Mice, Inbred BALB C; Mice, Nude; Organoids; Palbociclib; Patients; Phenotypes; Piperazines - pharmacology; Plasmids; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Receptors, Estrogen - metabolism; Recurrence (Disease); Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Scientific equipment industry; Survival analysis; Transcription (Genetics); Transcription activation; Tumor cell lines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; United States; China; lncRNA TROJAN; Breast cancer; CDK4/6 inhibitor
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-020-01210-9

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.