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

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 <i>FOXK2</i>, called circFOXK2, which plays a key role in stabilizing <i>CCND1</i> mRNA, thereby promoting cell cycle progression, cell growth, and endocrine therapy resistance in ER-positive breast cancer cells. Mechanistically, circFOXK2 binds directly to <i>CCND1</i> mRNA via RNA-RNA pairing and recruits the RNA-binding protein ELAVL1/HuR, stabilizing the <i>CCND1</i> 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 <i>CCND1</i> 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 <i>CCND1</i> and promoting cancer progression, positioning circFOXK2 as a potential therapeutic target for ER-positive breast cancer in clinical settings.