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HER2 抑制增加非肌肉肌球蛋白 IIA 以促进 HER2+乳腺癌的肿瘤发生。

HER2 inhibition increases non-muscle myosin IIA to promote tumorigenesis in HER2+ breast cancers.

机构信息

James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America.

Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.

出版信息

PLoS One. 2023 May 18;18(5):e0285251. doi: 10.1371/journal.pone.0285251. eCollection 2023.

DOI:10.1371/journal.pone.0285251
PMID:37200287
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10194889/
Abstract

HER2 is over-expressed in around 15% to 20% of breast cancers. HER3 plays a critical role in HER2 mediated tumorigenesis. Increased HER3 transcription and protein levels occur upon inhibition of HER2. We aimed to identify proteins that bound to HER3 upon inhibition of the HER family with the pan-HER inhibitor neratinib in HER2+ breast cancer cells. Immunoprecipitation of HER3 followed by mass spectrometry experiments found non-muscle myosin IIA (NMIIA) increased upon neratinib treatment relative to vehicle DMSO treatment. MYH9 is the gene that encodes for the heavy chain of NMIIA. Breast cancer patients with high MYH9 were significantly associated with a shorter disease specific survival compared to patients with low MYH9 expression from the METABRIC cohort of patients. In addition, high MYH9 expression was associated with HER2+ tumors from this cohort. Immunoblots of whole cell lysates of BT474 and MDA-MB-453 HER2+ breast cancer cells demonstrated elevated HER3 and NMIIA protein levels upon neratinib treatment for 24 hours. To examine the role of NMIIA in HER2+ breast cancer, we modulated NMIIA levels in BT474 and MDA-MB-453 cells using doxycycline inducible shRNA targeting MYH9. MYH9 knockdown reduces HER3 protein levels and concomitant reduction in downstream P-Akt. In addition, loss of MYH9 suppresses cell growth, proliferation, migration, and invasion. Our data reveals that NMIIA regulates HER3 and loss of NMIIA reduces HER2+ breast cancer growth.

摘要

HER2 在大约 15%至 20%的乳腺癌中过表达。HER3 在 HER2 介导的肿瘤发生中起着关键作用。HER2 抑制后，HER3 转录和蛋白水平增加。我们旨在鉴定在 HER2+乳腺癌细胞中用泛 HER 抑制剂奈拉替尼抑制 HER 家族后与 HER3 结合的蛋白质。HER3 的免疫沉淀后进行质谱实验发现，与 DMSO 处理的载体相比，奈拉替尼处理后非肌肉肌球蛋白 IIA（NMIIA）增加。MYH9 是编码 NMIIA 重链的基因。来自 METABRIC 队列的乳腺癌患者中，高 MYH9 的患者与低 MYH9 表达的患者相比，疾病特异性生存率显著降低。此外，来自该队列的 HER2+肿瘤与高 MYH9 表达相关。BT474 和 MDA-MB-453 HER2+乳腺癌细胞的全细胞裂解物免疫印迹显示，用奈拉替尼处理 24 小时后，HER3 和 NMIIA 蛋白水平升高。为了研究 NMIIA 在 HER2+乳腺癌中的作用，我们使用针对 MYH9 的 DOX 诱导 shRNA 调节 BT474 和 MDA-MB-453 细胞中的 NMIIA 水平。MYH9 敲低降低了 HER3 蛋白水平，并伴有下游 P-Akt 的减少。此外，MYH9 的缺失抑制了细胞生长、增殖、迁移和侵袭。我们的数据表明 NMIIA 调节 HER3，并且 NMIIA 的缺失减少了 HER2+乳腺癌的生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/d0585521b673/pone.0285251.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/9fe92cd99153/pone.0285251.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/5f0dd8176144/pone.0285251.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/a513748a89a9/pone.0285251.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/59b7b3f64466/pone.0285251.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/c2e772a020f3/pone.0285251.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/d0585521b673/pone.0285251.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/9fe92cd99153/pone.0285251.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/5f0dd8176144/pone.0285251.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/a513748a89a9/pone.0285251.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/59b7b3f64466/pone.0285251.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/c2e772a020f3/pone.0285251.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/10194889/d0585521b673/pone.0285251.g006.jpg

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引用本文的文献

[1]
Chicken Primordial Germ Cell Surface Marker.

Animals (Basel). 2025-6-24

[2]
Development of clinically viable non-muscle myosin II small molecule inhibitors.

Cell. 2025-6-27

[3]
Mapping Knowledge Landscapes and Themes Trends of Breast Cancer Stem Cells: A Comprehensive Data-Mining-Based Study.

Ann Surg Oncol. 2025-4-23

[4]
Correction: HER2 inhibition increases non-muscle myosin IIA to promote tumorigenesis in HER2+ breast cancers.

PLoS One. 2024-12-10

[5]
Unraveling MYH9-related disease: A case study on misdiagnosis with idiopathic thrombocytopenic purpura, confirmed through genetic.

Heliyon. 2024-8-13

[6]
Non-Muscle Myosin II A: Friend or Foe in Cancer?

Int J Mol Sci. 2024-8-30

[7]
Exploring the nexus between MYH9 and tumors: novel insights and new therapeutic opportunities.

Front Cell Dev Biol. 2024-8-1

本文引用的文献

[1]
Non-muscle myosin II isoforms orchestrate substrate stiffness sensing to promote cancer cell contractility and migration.

Cancer Lett. 2022-1-1

[2]
MYH9 is crucial for stem cell-like properties in non-small cell lung cancer by activating mTOR signaling.

Cell Death Discov. 2021-10-11

[3]
Trastuzumab deruxtecan and other HER2-targeting agents for the treatment of HER2-positive gastric cancer.

Expert Rev Anticancer Ther. 2021-11

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Drugs. 2021-4

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Clin Cancer Res. 2021-3-1

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MYH9 suppresses melanoma tumorigenesis, metastasis and regulates tumor microenvironment.

Med Oncol. 2020-9-9

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Cells. 2020-6-12

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Signal Transduct Target Ther. 2020-2-14

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Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance.

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