Mechanism of endoplasmic reticulum stress regulating doxorubicin resistance in breast cancer cells
SUN Jianing
WANG Jiajia
FAN Cong
JIA Lintao
WANG Ting
ZHANG Jian
Abstract：Objective To explore the mechanism of endoplasmic reticulum stress(ERS)in doxorubicin(DOX)resistance in breast cancer cells and provide theoretical support for clinical treatment.Methods Triple-negative breast cancer cells(MDA-MB-231,HCC1937)and non-triple-negative breast cancer cells(MCF-7,T47D)were taken as research subjects,parental cells(MDA-MB-231,MCF-7)as the control group,and the constructed DOX-resistant cell lines(MDA-MB-231/ADR,MCF-7/ADR)as the experimental group.The expression levels of ERS-related molecules were detected by RNA-Seq analysis,qRT-PCR,Western blotting and other methods.The impact of different ERS pathways on DOX sensitivity in breast cancer cells was investigated through inhibitor drug combination experiments(DOX combined with IRE1α inhibitor Kira6 or PERK inhibitor GSK2606414)and the construction of stable cell lines(MDA-MB-231 cell lines with XBP1 knockdown).Results The study found that the endoplasmic reticulum protein processing pathway was significantly enriched in different breast cancer cell lines,and the drug resistance mechanisms varied among different cell lines(P＜0.05).In triple-negative breast cancer cell lines,activation of the IRE1α-XBP1 pathway promoted DOX resistance by enhancing cellular autophagy levels.Conversely,in non-triple-negative breast cancer cell lines,activation of the PERK pathway played a critical role.Conclusion This study reveals the significant role of ERS in DOX resistance of breast cancer and provides a theoretical basis and potential targets for the targeted development of therapeutic strategies to reverse DOX resistance in breast cancer.
Keywords：endoplasmic reticulum stressbreast cancerdoxorubicindrug resistancetriple-negative breast cancerautophagyunfolded protein responsetumor cell line
Publication Date：2025-07-31
Online Publishing Date：2026-08-26(First online date of this platform, not the publication date of the document)
Pages：8( 887-894 )