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Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling
Malignant breast cancer (BC) remains incurable mainly due to the cancer cell metastasis, which is mostly related to the status of Estrogen receptor alpha (ERα). However, our understanding of the mechanisms through which ERα regulates cancer cell metastasis remains limited. Here we identified a miR-2...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10116798/ https://www.ncbi.nlm.nih.gov/pubmed/37081505 http://dx.doi.org/10.1186/s13046-023-02665-6 |
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author | Lü, Jinhui Zhao, Qian Guo, Yuefan Li, Danni Xie, Heying Liu, Cuicui Hu, Xin Liu, Suling Hou, Zhaoyuan wei, Xunbin Zheng, Deyou Pestell, Richard G. Yu, Zuoren |
author_facet | Lü, Jinhui Zhao, Qian Guo, Yuefan Li, Danni Xie, Heying Liu, Cuicui Hu, Xin Liu, Suling Hou, Zhaoyuan wei, Xunbin Zheng, Deyou Pestell, Richard G. Yu, Zuoren |
author_sort | Lü, Jinhui |
collection | PubMed |
description | Malignant breast cancer (BC) remains incurable mainly due to the cancer cell metastasis, which is mostly related to the status of Estrogen receptor alpha (ERα). However, our understanding of the mechanisms through which ERα regulates cancer cell metastasis remains limited. Here we identified a miR-29a-PTEN-AKT axis as a downstream signaling pathway of ERα governing breast cancer progression and metastasis. Two estrogen response element (ERE) half sites were identified in the promoter and enhancer regions of miR-29a, which mediated transcriptional regulation of miR-29a by ERα. Low level of miR-29a showed association with reduced metastasis and better survival in ERα+ luminal subtype of BC. In contrast, high level of miR-29a was detected in ERα- triple negative breast cancer (TNBC) in association with distant metastasis and poor survival. miR-29a overexpression in BC tumors increased the number of circulating tumor cells and promoted lung metastasis in mice. Targeted knockdown of miR-29a in TNBC cells in vitro or administration of a nanotechnology-based anti-miR-29a delivery in TNBC tumor-bearing mice in vivo suppressed cellular invasion, EMT and lung metastasis. PTEN was identified as a direct target of miR-29a, inducing EMT and metastasis via AKT signaling. A small molecular inhibitor of AKT attenuated miR-29a-induced EMT. These findings demonstrate a novel mechanism responsible for ERα-regulated breast cancer metastasis, and reveal the combination of ERα status and miR-29a levels as a new risk indicator in BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02665-6. |
format | Online Article Text |
id | pubmed-10116798 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-101167982023-04-21 Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling Lü, Jinhui Zhao, Qian Guo, Yuefan Li, Danni Xie, Heying Liu, Cuicui Hu, Xin Liu, Suling Hou, Zhaoyuan wei, Xunbin Zheng, Deyou Pestell, Richard G. Yu, Zuoren J Exp Clin Cancer Res Research Malignant breast cancer (BC) remains incurable mainly due to the cancer cell metastasis, which is mostly related to the status of Estrogen receptor alpha (ERα). However, our understanding of the mechanisms through which ERα regulates cancer cell metastasis remains limited. Here we identified a miR-29a-PTEN-AKT axis as a downstream signaling pathway of ERα governing breast cancer progression and metastasis. Two estrogen response element (ERE) half sites were identified in the promoter and enhancer regions of miR-29a, which mediated transcriptional regulation of miR-29a by ERα. Low level of miR-29a showed association with reduced metastasis and better survival in ERα+ luminal subtype of BC. In contrast, high level of miR-29a was detected in ERα- triple negative breast cancer (TNBC) in association with distant metastasis and poor survival. miR-29a overexpression in BC tumors increased the number of circulating tumor cells and promoted lung metastasis in mice. Targeted knockdown of miR-29a in TNBC cells in vitro or administration of a nanotechnology-based anti-miR-29a delivery in TNBC tumor-bearing mice in vivo suppressed cellular invasion, EMT and lung metastasis. PTEN was identified as a direct target of miR-29a, inducing EMT and metastasis via AKT signaling. A small molecular inhibitor of AKT attenuated miR-29a-induced EMT. These findings demonstrate a novel mechanism responsible for ERα-regulated breast cancer metastasis, and reveal the combination of ERα status and miR-29a levels as a new risk indicator in BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02665-6. BioMed Central 2023-04-20 /pmc/articles/PMC10116798/ /pubmed/37081505 http://dx.doi.org/10.1186/s13046-023-02665-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://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. |
spellingShingle | Research Lü, Jinhui Zhao, Qian Guo, Yuefan Li, Danni Xie, Heying Liu, Cuicui Hu, Xin Liu, Suling Hou, Zhaoyuan wei, Xunbin Zheng, Deyou Pestell, Richard G. Yu, Zuoren Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling |
title | Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling |
title_full | Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling |
title_fullStr | Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling |
title_full_unstemmed | Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling |
title_short | Regulation of ERα-dependent breast cancer metastasis by a miR-29a signaling |
title_sort | regulation of erα-dependent breast cancer metastasis by a mir-29a signaling |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10116798/ https://www.ncbi.nlm.nih.gov/pubmed/37081505 http://dx.doi.org/10.1186/s13046-023-02665-6 |
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