EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells

Abstract Transforming growth factor beta (TGF-β) is the main cytokine responsible for the induction of the epithelial-mesenchymal transition of breast cancer cells, which is a hallmark of tumor transformation to the metastatic phenotype. Recently, research demonstrated that the chemokine CCL2 gene e...

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Autores principales:	Alisa M. Gorbacheva, Aksinya N. Uvarova, Alina S. Ustiugova, Arindam Bhattacharyya, Kirill V. Korneev, Dmitry V. Kuprash, Nikita A. Mitkin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3f04f0958de149dda9d153af34e0a963
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spelling	oai:doaj.org-article:3f04f0958de149dda9d153af34e0a9632021-12-02T15:22:57ZEGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells10.1038/s41598-021-93561-62045-2322https://doaj.org/article/3f04f0958de149dda9d153af34e0a9632021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93561-6https://doaj.org/toc/2045-2322Abstract Transforming growth factor beta (TGF-β) is the main cytokine responsible for the induction of the epithelial-mesenchymal transition of breast cancer cells, which is a hallmark of tumor transformation to the metastatic phenotype. Recently, research demonstrated that the chemokine CCL2 gene expression level directly correlates with the TGF-β activity in breast cancer patients. CCL2 attracts tumor-associated macrophages and is, therefore, considered as an important inductor of breast cancer progression; however, the precise mechanisms underlying its regulation by TGF-β are unknown. Here, we studied the behavior of the CCL2 gene in MDA-MB-231 and HCC1937 breast cancer cells representing mesenchymal-like phenotype activated by TGF-β. Using bioinformatics, deletion screening and point mutagenesis, we identified binding sites in the CCL2 promoter and candidate transcription factors responsible for its regulation by TGF-β. Among these factors, only the knock-down of EGR1 and RXRA made CCL2 promoter activity independent of TGF-β. These factors also demonstrated binding to the CCL2 promoter in a TGF-β-dependent manner in a chromatin immunoprecipitation assay, and point mutations in the EGR1 and RXRA binding sites totally abolished the effect of TGF-β. Our results highlight the key role of EGR1 and RXRA transcription factors in the regulation of CCL2 gene in response to TGF-β pathway.Alisa M. GorbachevaAksinya N. UvarovaAlina S. UstiugovaArindam BhattacharyyaKirill V. KorneevDmitry V. KuprashNikita A. MitkinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alisa M. Gorbacheva Aksinya N. Uvarova Alina S. Ustiugova Arindam Bhattacharyya Kirill V. Korneev Dmitry V. Kuprash Nikita A. Mitkin EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells
description	Abstract Transforming growth factor beta (TGF-β) is the main cytokine responsible for the induction of the epithelial-mesenchymal transition of breast cancer cells, which is a hallmark of tumor transformation to the metastatic phenotype. Recently, research demonstrated that the chemokine CCL2 gene expression level directly correlates with the TGF-β activity in breast cancer patients. CCL2 attracts tumor-associated macrophages and is, therefore, considered as an important inductor of breast cancer progression; however, the precise mechanisms underlying its regulation by TGF-β are unknown. Here, we studied the behavior of the CCL2 gene in MDA-MB-231 and HCC1937 breast cancer cells representing mesenchymal-like phenotype activated by TGF-β. Using bioinformatics, deletion screening and point mutagenesis, we identified binding sites in the CCL2 promoter and candidate transcription factors responsible for its regulation by TGF-β. Among these factors, only the knock-down of EGR1 and RXRA made CCL2 promoter activity independent of TGF-β. These factors also demonstrated binding to the CCL2 promoter in a TGF-β-dependent manner in a chromatin immunoprecipitation assay, and point mutations in the EGR1 and RXRA binding sites totally abolished the effect of TGF-β. Our results highlight the key role of EGR1 and RXRA transcription factors in the regulation of CCL2 gene in response to TGF-β pathway.
format	article
author	Alisa M. Gorbacheva Aksinya N. Uvarova Alina S. Ustiugova Arindam Bhattacharyya Kirill V. Korneev Dmitry V. Kuprash Nikita A. Mitkin
author_facet	Alisa M. Gorbacheva Aksinya N. Uvarova Alina S. Ustiugova Arindam Bhattacharyya Kirill V. Korneev Dmitry V. Kuprash Nikita A. Mitkin
author_sort	Alisa M. Gorbacheva
title	EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells
title_short	EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells
title_full	EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells
title_fullStr	EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells
title_full_unstemmed	EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells
title_sort	egr1 and rxra transcription factors link tgf-β pathway and ccl2 expression in triple negative breast cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3f04f0958de149dda9d153af34e0a963
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EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells

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