| Item type |
文献 / Documents(1) |
| 公開日 |
2024-10-07 |
| アクセス権 |
|
|
アクセス権 |
open access |
|
アクセス権URI |
http://purl.org/coar/access_right/c_abf2 |
| 資源タイプ |
|
|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
関連識別子 |
https://doi.org/10.1186/s13046-023-02715-z |
|
|
関連名称 |
10.1186/s13046-023-02715-z |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer |
| 著者 |
de Heer, E. C.
Zois, C. E.
Bridges, E.
van der Vegt, B.
Sheldon, H.
Veldman, W. A.
Zwager, M. C.
van der Sluis, T.
Haider, S.
守田, 剛
馬場, 麻人
Schröder, C. P.
de Jong, S.
Harris, A. L.
Jalving, M.
|
| 抄録 |
|
|
内容記述 |
Background
Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models.
Methods
mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs.
Results
High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53–121) and other Ki67-high tumors (median H-score 85, IQR 57–124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis.
Conclusions
Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets. |
| キーワード |
|
|
主題 |
Glycogen synthase 1 |
| キーワード |
|
|
主題 |
Breast cancer |
| キーワード |
|
|
主題 |
Glycogen |
| キーワード |
|
|
主題 |
Mitochondria |
| キーワード |
|
|
主題 |
Ki67 |
| 書誌情報 |
en : Journal of Experimental & Clinical Cancer Research
巻 42,
p. 143,
発行日 2023-06-06
|
| 収録物ID |
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|
収録物識別子タイプ |
ISSN |
|
収録物識別子 |
17569966 |
| 出版者 |
|
|
出版者 |
Springer Nature |
| 出版者 |
|
|
出版者 |
BioMed Central |
| 権利情報 |
|
|
権利情報 |
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| EID |
|
|
識別子 |
407028 |
| 言語 |
|
|
言語 |
eng |
jeccr_42_143.pdf (6.5 MB)
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