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DAB2IP 通过隔离 RAC1 来防止β-连环蛋白核积累，从而减弱三阴性乳腺癌的化疗耐药性。

DAB2IP attenuates chemoresistance of triple-negative breast cancer through sequestration of RAC1 to prevent β-catenin nuclear accumulation.

机构信息

Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

出版信息

Clin Transl Med. 2022 Dec;12(12):e1133. doi: 10.1002/ctm2.1133.

DOI:10.1002/ctm2.1133
PMID:36536485
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9763535/
Abstract

BACKGROUND: Although chemotherapy, the most widely used systemic treatment in triple-negative breast cancer (TNBC), markedly improved the patients' outcome, chemoresistance always occurs. This study purposed to explore new therapeutic strategies for the treatment of chemoresistance. METHODS AND RESULTS: The expression and prognostic value of DAB2IP were investigated in TNBC tissues and cell lines. Low DAB2IP expression predicted high mortality risk in TNBC. Inhibition of DAB2IP expression conferred cancer stem cell capacity and chemoresistance in TNBC cell lines. Using murine breast cancer (BC) xenograft models, we evaluated the association with DAB2IP and chemoresistance. DAB2IP inhibited TNBC tumourigenesis and chemoresistance in vivo. Further, we revealed that DAB2IP inhibited β-catenin nuclear transport through competitive interaction with RAC1 and decreased β-catenin accumulation in the cell nucleus. Finally, we found that the DNA methylation level was negatively associated with DAB2IP expression in TNBC. Inhibition of DNA methylation restored the DAB2IP expression and attenuated chemoresistance in TNBC. CONCLUSIONS: We revealed that DAB2IP attenuates chemoresistance of TNBC via inhibition of RAC1-mediated β-catenin nuclear accumulation. Decitabine treatment results in re-expression of DAB2IP by inhibiting DNA methylation and could be a potential therapeutic strategy for chemoresistance in TNBC.

摘要

背景：尽管化疗是三阴性乳腺癌（TNBC）最广泛使用的全身性治疗方法，但它显著改善了患者的预后，但化疗耐药性总是会发生。本研究旨在探索治疗化疗耐药性的新治疗策略。

方法和结果：研究了 DAB2IP 在 TNBC 组织和细胞系中的表达及其预后价值。低 DAB2IP 表达预示着 TNBC 患者的死亡率较高。抑制 DAB2IP 表达可赋予 TNBC 细胞系的癌症干细胞能力和化疗耐药性。我们使用小鼠乳腺癌（BC）异种移植模型评估了 DAB2IP 与化疗耐药性的相关性。DAB2IP 抑制 TNBC 肿瘤发生和体内化疗耐药性。此外，我们揭示 DAB2IP 通过与 RAC1 的竞争相互作用抑制 β-连环蛋白核转运，并减少细胞内 β-连环蛋白的积累。最后，我们发现 DNA 甲基化水平与 TNBC 中的 DAB2IP 表达呈负相关。抑制 DNA 甲基化可恢复 DAB2IP 的表达并减弱 TNBC 的化疗耐药性。

结论：我们揭示 DAB2IP 通过抑制 RAC1 介导的 β-连环蛋白核积累来减轻 TNBC 的化疗耐药性。地西他滨治疗通过抑制 DNA 甲基化导致 DAB2IP 的重新表达，可能是 TNBC 化疗耐药性的一种潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/23b771d6d5a4/CTM2-12-e1133-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/4c431a5591ae/CTM2-12-e1133-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/75468cb85f55/CTM2-12-e1133-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/cb28f34854fa/CTM2-12-e1133-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/715cce826c8a/CTM2-12-e1133-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/500fef312d27/CTM2-12-e1133-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/ddf74f26b6ca/CTM2-12-e1133-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/3a2532968e5c/CTM2-12-e1133-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/23b771d6d5a4/CTM2-12-e1133-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/4c431a5591ae/CTM2-12-e1133-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/75468cb85f55/CTM2-12-e1133-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/cb28f34854fa/CTM2-12-e1133-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/715cce826c8a/CTM2-12-e1133-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/500fef312d27/CTM2-12-e1133-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/ddf74f26b6ca/CTM2-12-e1133-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/3a2532968e5c/CTM2-12-e1133-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79f2/9763535/23b771d6d5a4/CTM2-12-e1133-g009.jpg

相似文献

[1]
DAB2IP attenuates chemoresistance of triple-negative breast cancer through sequestration of RAC1 to prevent β-catenin nuclear accumulation.

Clin Transl Med. 2022-12

[2]
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Oncotarget. 2017-1-10

[3]
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Breast Cancer Res. 2023-3-22

[4]
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[5]
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[6]
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[7]
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Cell Oncol (Dordr). 2020-8

[8]
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Clin Cancer Res. 2013-7-9

[9]
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[10]
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Clin Transl Oncol. 2021-4

引用本文的文献

[1]
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Acta Pharm Sin B. 2025-5

[2]
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Cell Death Differ. 2024-7

[3]
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Mol Biol Rep. 2024-6-1

[4]
Disable 2, A Versatile Tissue Matrix Multifunctional Scaffold Protein with Multifaceted Signaling: Unveiling Role in Breast Cancer for Therapeutic Revolution.

Cell Biochem Biophys. 2024-6

[5]
Disabled-2, a versatile tissue matrix multifunctional scaffold protein with multifaceted signaling: Unveiling its potential in the cancer battle.

Naunyn Schmiedebergs Arch Pharmacol. 2024-8

[6]
Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection.

Front Immunol. 2024

[7]
The Tumor Suppressor DAB2IP Is Regulated by Cell Contact and Contributes to YAP/TAZ Inhibition in Confluent Cells.

Cancers (Basel). 2023-6-27

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