Quercetin inhibits the epithelial-mesenchymal transition and reverses CDK4/6 inhibitor resistance in breast cancer by regulating circHIAT1/miR-19a-3p/CADM2 axis

Sep 21, 2026

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Breast cancer progression is driven by epithelial-mesenchymal transition (EMT), and Palbociclib (a CDK4/6 inhibitor) can be limited by drug resistance and metastasis. This study evaluates the circHIAT1/miR-19a-3p/CADM2 axis in regulating EMT and Palbociclib resistance in breast cancer. circHIAT1 and CADM2 are decreased, while miR-19a-3p is increased, in patient tissues and cell lines. circHIAT1 suppresses miR-19a-3p activity and thereby modulates CADM2, reducing EMT and migration; these effects are blocked by miR-19a-3p mimic. In Palbociclib-resistant cells, circHIAT1 re-expression restores Palbociclib sensitivity. Quercetin further inhibits migration and invasion and re-sensitizes cells via upregulating circHIAT1, with in vivo tumorigenesis confirming enhanced Palbociclib anti-tumor efficacy dependent on circHIAT1 upregulation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Abstract

Introduction

Breast cancer EMT and metastasis

CDK4/6, Palbociclib, and acquired resistance

Rationale for targeting circHIAT1/miR-19a-3p/CADM2

PLOS ONE OPEN ACCESS Citation: Li X, Niu C, Yi G, Zhang Y, Jin W, Zhang Z, et al. (2024) Quercetin inhibits the epithelialmesenchymal transition and reverses CDK4/6 inhibitor resistance in breast cancer by regulating circHIAT1/miR-19a-3p/CADM2 axis. PLoS ONE 19(7): e0305612 . [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pone.0305612 Editor: Wei Xu, University of Wisconsin-Madison, UNITED STATES Received: December 21, 2023 Accepted: May 31, 2024 Published: July 11, 2024 Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data supporting the findings of this study are available from the Mendeley data repository ([https://data.mendeley](https://data.mendeley). com/datasets/pm2vrt97xx/1) . Funding: The following funds are gratefully acknowledged for supporting this study: the Medical Reserve Talent Program of Yunnan Provincial Health Commission (NO. H-2018064); Scientific Research Fund Project of Education Department of Yunnan Province (2023J0046) . The RESEARCH ARTICLE Quercetin inhibits the epithelial-mesenchymal transition and reverses CDK4/6 inhibitor resistance in breast cancer by regulating circHIAT1/miR-19a-3p/CADM2 axis Xiaogang Li‡, Chao Niu‡, Guoqiang Yi, Yuan Zhang, Wendi Jin, Zhiping Zhang, Wanfu Zhang*, Bo Li * Department of General Surgery, Affiliated Hospital of Yunnan University, Kunming, Yunnan, China ‡ XL and CN are contributed equally to this work as co-first authors. * [920397zwf@163.com](920397zwf@163.com) (WZ); [libo2345442@126.com](libo2345442@126.com) (BL) Abstract Breast cancer (BC) cells have a high risk of metastasis due to epithelial-mesenchymal transition (EMT) . Palbociclib (CDK4/6 inhibitor) is an approved drug for BC treatment. However, the drug resistance and metastasis can impair the treatment outcome of Palbociclib. Understanding the mechanisms of EMT and Palbociclib drug resistance in BC is conducive to the formulation of novel therapeutic strategy. Here, we investigated the role of circHIAT1/miR- 19a-3p/CADM2 axis in modulating EMT and Palbociclib resistance in BC. circHIAT1 and CADM2 were down-regulated in BC tissues and cell lines, and miR-19a-3p showed an upregulation. circHIAT1 could interact with miR-19a-3p and suppress its activity, while miR- 19a-3p functioned to negatively regulate CADM2 . Forced over-expression of circHIAT1 could impaired the EMT status and migratory ability of BC cells, and this effect was inhibited by miR-19a-3p mimic. In addition, we also generated Palbociclib resistant BC cells, and showed that circHIAT1 and CADM2 were down-regulated in the resistant BC cells while miR-19a-3p showed an up-regulation. Forced circHIAT1 over-expression re-sensitized BC cells to Palbociclib treatment. Quercetin, a bioactive flavonoid, could suppressed the migration and invasion of BC cells, and re-sensitized BC cells to Palbociclib. The anti-cancer effect of quercetin could be attributed to its regulatory effect on circHIAT1/miR-19a-3p/ CADM2 axis. In vivo tumorigenesis experiment further revealed that quercetin administration enhanced the anti-cancer effect of Palbociclib, an effect was dependent on the up-regulation of circHIAT1 by quercetin. In summary, this study identified quercetin as a potential anti-cancer compound to reverse Palbociclib resistance and impair EMT in BC cells by targeting circHIAT1/miR-19a-3p/CADM2 axis. Introduction As the most prevalent malignancy and the top risk factor of cancer-related death in women, breast cancer (BC) is becoming a major health threat to female population [ 1, 2] . In spite of funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors hav

FAQs

What problem does the study address in breast cancer therapy?

The study targets EMT-driven metastasis and the eventual resistance that limits Palbociclib effectiveness in breast cancer.

How does circHIAT1 affect EMT and Palbociclib sensitivity?

circHIAT1 suppresses miR-19a-3p activity, leading to regulation of CADM2, impairment of EMT and migration, and re-sensitization of Palbociclib-resistant breast cancer cells.

What role does quercetin play according to the abstract?

Quercetin suppresses breast cancer cell migration and invasion and re-sensitizes cells to Palbociclib by upregulating circHIAT1, with in vivo results showing enhanced anti-cancer effects dependent on this increase.

Sep 21, 2026

Uploaded by Aria