AGEs induce MMP-9 promoter demethylation through the GADD45α-mediated BER pathway to promote breast cancer metastasis in patients with diabetes

in Endocrine-Related Cancer
Authors:
Liyan Zhou Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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https://orcid.org/0000-0001-7705-5091
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Guiying Bai Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yue Song Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Xiaohui Liu Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Xiaoqing Li Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yilin Deng Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yiran Si Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Yehui Shi Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Hongli Li Department of Phase I Clinical Trial, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

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Correspondence should be addressed to L Zhou: zhouliyan@tjmuch.com
DOI:
https://doi.org/10.1530/ERC-23-0330
Volume/Issue:
Volume 31: Issue 9
Article Type:
Research Article
Article ID:
e230330
Online Publication Date:
17 Jul 2024
Copyright:
© the author(s) 2024
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Scientific evidence has linked diabetes to a higher incidence and increased aggressiveness of breast cancer; however, mechanistic studies of the numerous regulators involved in this process are insufficiently thorough. Advanced glycation end products (AGEs) play an important role in the chronic complications of diabetes, but the mechanisms of AGEs in breast cancer are largely unexplored. In this study, we first demonstrate that high AGE levels in breast cancer tissues are associated with the diabetic state and poor patient outcomes. Furthermore, AGEs interact with the receptor for AGEs (RAGE) to promote breast cancer cell migration and invasion. Mechanistically, based on RNA sequencing (RNA-seq) analysis, we reveal that growth arrest and DNA damage gene 45α (GADD45α) is a vital protein upregulated by AGEs through a P53-dependent pathway. Next, GADD45α recruits thymine DNA glycosylase for base excision repair to form the demethylation complex at the promoter region of MMP-9 and enhance MMP-9 transactivation through DNA demethylation. Overall, our results indicate a critical regulatory role of AGEs in patients with breast cancer and diabetes and reveal a novel mechanism of epigenetic modification in promoting breast cancer metastasis.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© the author(s) 2024
Article ID:
e230330
Received Date:
27 Nov 2023
Accepted Date:
20 Jun 2024
Print Publication Date:
01 Sep 2024
Online Publication Date:
17 Jul 2024
Keywords:
breast cancer; diabetes; advanced glycation end products; matrix metalloproteinase-9; DNA demethylation

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