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乳腺癌细胞对激素疗法和靶向疗法的耐药性与NR6A1轴的失活相关。

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

作者信息

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

机构信息

N.N. Blokhin National Medical Research Center of Oncology, the Ministry of Health of Russia, Moscow 115522, Russia.

Authors contributed equally.

出版信息

Cancer Drug Resist. 2024 Nov 23;7:48. doi: 10.20517/cdr.2024.69. eCollection 2024.

DOI:10.20517/cdr.2024.69
PMID:39624078
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11609143/
Abstract

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. 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. 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. 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.

摘要

乳腺癌对激素疗法和靶向疗法的耐药性限制了治疗效果。表观遗传改变，包括由DNA甲基转移酶介导的变化，在这一过程中起关键作用。此前，我们发现对他莫昔芬和雷帕霉素的耐药性与DNMT3A的抑制有关。本研究旨在进一步探究这种抑制作用的潜在机制，重点是确定NR6A1为一种新的调节因子。获取耐药乳腺癌细胞亚系、MTT试验、免疫印迹、瞬时转染和报告基因分析、慢病毒感染、qRT-PCR以及使用亚硫酸氢盐焦磷酸测序法进行甲基化分析。我们的研究结果表明，乳腺癌细胞对激素疗法和靶向疗法产生交叉耐药性的过程涉及细胞信号转导向替代AKT途径的转变，其特征是NR6A1/DNMT3A轴的局部抑制以及相关的DNA甲基化变化。我们证明了NR6A1下调在耐药性形成中的关键作用。此外，我们观察到上皮-间质转化的关键调节因子Snail的激活是NR6A1缺失效应的介导因素，从而建立了Snail表达与耐药性形成之间的直接联系。NR6A1和DNMT3A的协同抑制可能有助于维持乳腺癌细胞的耐药表型。这一途径可作为一种预测标志物，有助于指导未来乳腺癌治疗中最佳治疗策略的选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/55d886301d36/cdr-7-48.fig.7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/33ee76c88696/cdr-7-48.fig.1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/698cf8a4bf7d/cdr-7-48.fig.2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/6e7480a777a1/cdr-7-48.fig.5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/8427aeecad29/cdr-7-48.fig.6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/55d886301d36/cdr-7-48.fig.7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/33ee76c88696/cdr-7-48.fig.1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/698cf8a4bf7d/cdr-7-48.fig.2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/56605f97c787/cdr-7-48.fig.3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/bf4bed6c3e42/cdr-7-48.fig.4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/6e7480a777a1/cdr-7-48.fig.5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/8427aeecad29/cdr-7-48.fig.6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/042c/11609143/55d886301d36/cdr-7-48.fig.7.jpg

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