Breast cancer cell resistance to hormonal and targeted therapeutics is correlated with the inactivation of the NR6A1 axis  

作　　者：Olga E.Andreeva Danila V.Sorokin Svetlana V.Vinokurova Pavel B.Kopnin Nadezhda V.Elkina Alexey N.Katargin Radik S.Faskhutdinov Diana I.Salnikova Alexander M.Scherbakov Mikhail A.Krasil’nikov 

机构地区：[1]N.N.Blokhin National Medical Research Center of Oncology,the Ministry of Health of Russia,Moscow 115522,Russia [2]Gause Institute of New Antibiotics,Moscow 119021,Russia

出　　处：《Cancer Drug Resistance》2024年第1期126-141,共16页癌症耐药(英文)

基　　金：supported by the Russian Science Foundation(project No.24-15-00173,https://rscf.ru/project/24-15-00173/).

摘　　要：Aim:Resistance to hormonal and targeted therapies in breast cancer limits treatment efficacy.Epigenetic alterations,including changes mediated by DNA methyltransferases,play a key role in this process.Previously,we identified that resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.This study aims to further explore the mechanisms underlying this suppression,with a focus on identifying NR6A1 as a novel regulatory factor.Methods:Acquisition of resistant breast cancer cell sublines,MTT-test,immunoblotting,transient transfection and reporter analysis,lentiviral infection,qRT-PCR,and analysis of methylation using bisulfite pyrosequencing.Results:Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways,marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes.We demonstrated the critical role of NR6A1 downregulation in resistance development.Additionally,we observed activation of Snail-a key regulator in the epithelial-mesenchymal transition-as a mediator of the effects of NR6A1 depletion,establishing a direct link between Snail expression and resistance formation.Conclusion:The coordinated suppression of NR6A1 and DNMT3A may contribute to sustaining the resistant phenotype in breast cancer cells.This pathway could serve as a predictive marker,helping guide the selection of optimal therapeutic strategies for breast cancer treatment in the future.

关 键 词：Breast cancer TAMOXIFEN RAPAMYCIN METHYLATION DNMT3A NR6A1 SNAIL estrogen receptorα MCF-7 cells 

分 类 号：R73[医药卫生—肿瘤]