EGR1 and RXRA transcription factors link TGF-ß pathway and CCL2 expression in triple negative breast cancer cells.
Sci Rep
; 11(1): 14120, 2021 07 08.
Article
em En
| MEDLINE
| ID: mdl-34239022
ABSTRACT
Transforming growth factor beta (TGF-ß) 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-ß 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-ß 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-ß. 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-ß. Among these factors, only the knock-down of EGR1 and RXRA made CCL2 promoter activity independent of TGF-ß. These factors also demonstrated binding to the CCL2 promoter in a TGF-ß-dependent manner in a chromatin immunoprecipitation assay, and point mutations in the EGR1 and RXRA binding sites totally abolished the effect of TGF-ß. Our results highlight the key role of EGR1 and RXRA transcription factors in the regulation of CCL2 gene in response to TGF-ß pathway.
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1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Fator de Crescimento Transformador beta
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Quimiocina CCL2
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Receptor X Retinoide alfa
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Proteína 1 de Resposta de Crescimento Precoce
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Neoplasias de Mama Triplo Negativas
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article