# The Interaction of CircESR1 and HNRNPAB Regulates Cell Cycle Transition of Breast Cancer Cell

## TL;DR

This study identifies a new circular RNA, circESR1, and its interaction with HNRNPAB that promotes breast cancer progression and resistance to treatment.

## Contribution

The study reveals a novel circESR1-HNRNPAB signaling complex that regulates cell cycle and drug resistance in ER+ breast cancer.

## Key findings

- CircESR1 and HNRNPAB form a positive feedback loop promoting antiestrogen resistance in breast cancer cells.
- HNRNPAB stabilizes CDK1 and CDK6 mRNA to drive cell cycle progression in breast cancer.
- High levels of circESR1 and HNRNPAB correlate with poor prognosis and advanced cancer stages in patients.

## Abstract

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, circESR1 was identified as a novel circRNA exhibiting high specificity of expression in ER+ breast cancer. CircESR1 interacted with HNRNPAB, which was transcriptionally activated by ER/SP1 signaling. HNRNPAB promoted the back-splicing and expression of circESR1 by binding to the Alu elements of cognate pre-mRNA; and circESR1 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 CDK1 and CDK6 mRNA, which was facilitated by its asymmetrical binding of circESR1, to promote cell cycle progression. Patients whose cancer exhibited high levels of circESR1 and/or HNRNPAB exhibited advanced prognostic stage and poor survival. Combined use of circESR1 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 circESR1 and HNRNPAB in ER+ breast cancer, and suggested that circESR1 might represent a potential therapeutic target for this disease.