A circRNA-mRNA pairing mechanism regulates tumor growth and endocrine therapy resistance in ER- positive breast cancer

• 成果类型: Article
• 署名作者: Yi, Jia; Du, Jiao; Chen, Xue; Nie, Rui-chao; Hu, Guo-sheng; Wang, Lei; Zhang, Yue-ying; Chen, Shang; Wen, Xiao-sha; Luo, Di-xian; He, Hua; Liu, Wen
• 署名单位: Xiamen University; Xiamen University; Xiamen University; Jinfeng Laboratory; Xiamen University; Shenzhen University; Naval Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14574
• DOI: 10.1073/pnas.2420383122
• 发表日期: 2025-02-18
• 关键词: cell-cycle progression; circular rnas; retinoblastoma protein; noncoding rna; d1; overexpression; cyclin-d1; polymorphism; expression; tamoxifen

摘要

The molecular mechanisms underlying estrogen receptor (ER)- positive breast carcinogenesis and drug resistance remain incompletely understood. Elevated expression of CCND1 is linked to enhanced invasiveness, poorer prognosis, and resistance to drug therapies in ER- positive breast cancer. In this study, we identify a highly expressed circular RNA (circRNA) derived from FOXK2, called circFOXK2, which plays a key role in stabilizing CCND1 mRNA, thereby promoting cell cycle progression, cell growth, and endocrine therapy resistance in ER- positive breast cancer cells. Mechanistically, circFOXK2 binds directly to CCND1 mRNA via RNA-RNA pairing and recruits the RNA- binding protein ELAVL1/HuR, stabilizing the CCND1 mRNA and enhancing CCND1 protein levels. This results in activation of the CCND1-CDK4/6-p-RB-E2F signaling axis, driving the transcription of downstream E2F target genes and facilitating the G1/S transition during cell cycle progression. Notably, targeting circFOXK2 with antisense oligonucleotide (ASO- circFOXK2) suppresses ER- positive breast cancer cell growth both in vitro and in vivo. Moreover, combination therapy with ASO- circFOXK2 and tamoxifen exhibits synergistic effects and restores tamoxifen sensitivity in tamoxifen- resistant cells. Clinically, high circFOXK2 expression is positively correlated with CCND1 levels in both ER- positive breast cancer cell lines and patient tumor tissues. Overall, our findings reveal the critical role of circFOXK2 in stabilizing the oncogene CCND1 and promoting cancer progression, positioning circFOXK2 as a potential therapeutic target for ER- positive breast cancer in clinical settings.