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 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.

Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer

“…Details on the IHC protocol have been described previously [ 32 – 34 ]. For haematoxylin and eosin (H&E) staining, slides were stained with Mayer’s haematoxylin (Sigma-Aldrich) and 0.1% sodium bicarbonate and counterstained with Eosin Y solution (Sigma-Aldrich).…”

Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

“…Cornell et al demonstrated that miR-432-5p–mediated suppression of the TGF-β signaling pathway via SMAD4 knockdown and increased CDK6 expression, thus conferring transmissible and reversible CDK4/6 inhibitor adaptation ( Cornell et al, 2019 ). In addition, a recent study showed that LncRNA TROJAN could mediate resistance to CDK4/6 inhibitors by increasing CDK2 activation in ER+ breast cancer ( Jin et al, 2020 ). Analysis of patient plasma exosomes may identify emerging resistance mechanisms.…”

Progress of Breast Cancer basic research in China

“…In terms of targeted therapy, lncRNA TINCR induces trastuzumab resistance by regulating miR-125b/HER-2 (human epidermal growth factor receptor 2) pathways 63 . LncRNA TROJAN promotes ER+ breast cancer resistance to palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, through TROJAN-NKRF-CDK2 axis 64 . PARP inhibitor olaparib is effective in treating breast cancer patients with BRCA1 mutations.…”