利用接近标记绘制ER+乳腺癌细胞中的FOXA1相互作用组揭示了与孤儿核受体NR2C2的新相互作用。

IF 4.7 2区 医学 Q2 CELL BIOLOGY
Rosemary N Plagens, Carla S Rodriquez Tirado, Shen Li, Natalia Maldonado-Vazquez, Ingrid M Montes-Rodriguez, Julie Dutil, Christine A Mills, Laura E Herring, Hector L Franco
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引用次数: 0

摘要

FOXA1是激素驱动型癌症中染色质可及性和转录调控必不可少的先驱转录因子。在乳腺癌中,FOXA1在促进核受体结合、重编程增强子景观和促进与治疗耐药性相关的转录变化中发挥核心作用。虽然FOXA1的功能主要是在雌激素受体-α (ER)的背景下研究的,但其更广泛的蛋白质相互作用网络仍然不完全确定。在这里,我们使用邻近依赖生物素标记(miniTurbo)结合定量LC-MS/MS蛋白质组学,系统地绘制了er阳性乳腺癌细胞中foxa1相互作用蛋白的图谱。我们设计了MCF-7细胞系,在n端或c端稳定表达minitturbo标记的FOXA1,以确保相互作用界面的全面覆盖。该方法恢复了已知的FOXA1合作伙伴,包括AR、MLL3、YAP1和GATA3,并确定了157个以前未报道的FOXA1相互作用子。值得注意的是,在ER+乳腺癌患者中,包括NR2C2在内的42种新伴侣与较差的无复发生存率显著相关。为了证明这一资源的实用性,我们深入描述了FOXA1-NR2C2相互作用。整合ChIP-seq和RNA-seq,我们发现FOXA1和NR2C2共同占据基因组区域的一个子集,并驱动参与肿瘤进展的共调节转录程序。我们的研究揭示了FOXA1相互作用组的扩展及其在乳腺癌中的功能网络的新见解,为进一步探索作为生物标志物或治疗靶点的候选蛋白提供了新的见解。意义:这些发现扩大了FOXA1相互作用组在乳腺癌中的作用,并发现了新的候选蛋白,它们有可能作为激素驱动肿瘤的生物标志物和治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mapping the FOXA1 Interactome in ER+ Breast Cancer Cells using Proximity Labeling Reveals Novel Interactions with the Orphan Nuclear Receptor NR2C2.

FOXA1 is a pioneer transcription factor essential for chromatin accessibility and transcriptional regulation in hormone-driven cancers. In breast cancer, FOXA1 plays a central role in facilitating nuclear receptor binding, reprogramming enhancer landscapes, and promoting transcriptional changes associated with therapy resistance. While FOXA1's function has been primarily studied in the context of estrogen receptor-α (ER), its broader protein interaction network remains incompletely defined. Here, we systematically map FOXA1-interacting proteins in ER-positive breast cancer cells using proximity-dependent biotin labeling (miniTurbo) combined with quantitative LC-MS/MS proteomics. We engineered MCF-7 cell lines stably expressing miniTurbo-tagged FOXA1 at either the N-terminus or C-terminus to ensure comprehensive coverage of interaction interfaces. This approach recovered known FOXA1 partners, including AR, MLL3, YAP1, and GATA3, and identified 157 previously unreported FOXA1 interactors. Notably, 42 of these novel partners, including NR2C2, were significantly associated with poor relapse-free survival in ER+ breast cancer patients. To demonstrate the utility of this resource, we characterized the FOXA1-NR2C2 interaction in depth. Integrating ChIP-seq and RNA-seq, we show that FOXA1 and NR2C2 co-occupy a subset of genomic regions and drive co-regulated transcriptional programs involved in tumor progression. Our study reveals an expanded FOXA1 interactome and new insights into its functional network in breast cancer, providing candidate proteins for further exploration as biomarkers or therapeutic targets. Implications: These findings expand the FOXA1 interactome in breast cancer and uncover new candidate proteins with potential as biomarkers and therapeutic targets in hormone-driven tumors.

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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
期刊介绍: Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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