The Interaction of <i>CircESR1</i> and HNRNPAB Regulates Cell Cycle Transition of Breast Cancer Cell

The mechanisms by which circRNAs regulate estrogen receptor (ER)-positive breast progression and therapeutic resistance remain poorly defined. By screening circRNAs involved in ER signaling, <i>circESR1</i> was identified as a novel circRNA exhibiting high specificity of expression in ER+ breast cancer. <i>CircESR1</i> interacted with HNRNPAB, which was transcriptionally activated by ER/SP1 signaling. HNRNPAB promoted the back-splicing and expression of <i>circESR1</i> by binding to the Alu elements of cognate pre-mRNA; and <i>circESR1</i> transcripts increased the stability and expression of HNRNPAB, ensuring an efficient positive feedback loop as reflected in antiestrogen-resistant breast cancer cells. Furthermore, HNRNPAB interacted and stabilized <i>CDK1</i> and <i>CDK6</i> mRNA, which was facilitated by its asymmetrical binding of <i>circESR1</i>, to promote cell cycle progression. Patients whose cancer exhibited high levels of <i>circESR1</i> and/or HNRNPAB exhibited advanced prognostic stage and poor survival. Combined use of <i>circESR1</i> ASO and CDK4/6 inhibitors were shown to be an effective therapeutic approach overcoming antiestrogen resistance in breast cancer xenograft models. Hence, these findings elucidated a novel signaling complex centered around <i>circESR1</i> and HNRNPAB in ER+ breast cancer, and suggested that <i>circESR1</i> might represent a potential therapeutic target for this disease.