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GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer

Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated...

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Autores principales: Bai, Feng, Zhang, Li-Han, Liu, Xiong, Wang, Chuying, Zheng, Chenglong, Sun, Jianping, Li, Min, Zhu, Wei-Guo, Pei, Xin-Hai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344017/
https://www.ncbi.nlm.nih.gov/pubmed/34373738
http://dx.doi.org/10.7150/thno.59280
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author Bai, Feng
Zhang, Li-Han
Liu, Xiong
Wang, Chuying
Zheng, Chenglong
Sun, Jianping
Li, Min
Zhu, Wei-Guo
Pei, Xin-Hai
author_facet Bai, Feng
Zhang, Li-Han
Liu, Xiong
Wang, Chuying
Zheng, Chenglong
Sun, Jianping
Li, Min
Zhu, Wei-Guo
Pei, Xin-Hai
author_sort Bai, Feng
collection PubMed
description Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated that BRCA1 suppresses EMT and regulates the expression of multiple EMT-related transcription factors. However, the downstream mediators of BRCA1 function in EMT suppression remain elusive. Methods: Depletion of BRCA1 or GATA3 activates p18(INK4C), a cell cycle inhibitor which inhibits mammary epithelial cell proliferation. We have therefore created genetically engineered mice with Brca1 or Gata3 loss in addition to deletion of p18(INK4C), to rescue proliferative defects caused by deficiency of Brca1 or Gata3. By using these mutant mice along with human BRCA1 deficient as well as proficient breast cancer tissues and cells, we investigated and compared the role of Brca1 and Gata3 loss in the activation of EMT in breast cancers. Results: We discovered that BRCA1 and GATA3 expressions were positively correlated in human breast cancer. Depletion of BRCA1 stimulated methylation of GATA3 promoter thereby repressing GATA3 transcription. We developed Brca1 and Gata3 deficient mouse system. We found that Gata3 deficiency in mice induced poorly-differentiated mammary tumors with the activation of EMT and promoted tumor initiating and metastatic potential. Gata3 deficient mammary tumors phenocopied Brca1 deficient tumors in the induction of EMT under the same genetic background. Reconstitution of Gata3 in Brca1-deficient tumor cells activated mesenchymal-epithelial transition, suppressing tumor initiation and metastasis. Conclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis.
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spelling pubmed-83440172021-08-08 GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer Bai, Feng Zhang, Li-Han Liu, Xiong Wang, Chuying Zheng, Chenglong Sun, Jianping Li, Min Zhu, Wei-Guo Pei, Xin-Hai Theranostics Research Paper Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated that BRCA1 suppresses EMT and regulates the expression of multiple EMT-related transcription factors. However, the downstream mediators of BRCA1 function in EMT suppression remain elusive. Methods: Depletion of BRCA1 or GATA3 activates p18(INK4C), a cell cycle inhibitor which inhibits mammary epithelial cell proliferation. We have therefore created genetically engineered mice with Brca1 or Gata3 loss in addition to deletion of p18(INK4C), to rescue proliferative defects caused by deficiency of Brca1 or Gata3. By using these mutant mice along with human BRCA1 deficient as well as proficient breast cancer tissues and cells, we investigated and compared the role of Brca1 and Gata3 loss in the activation of EMT in breast cancers. Results: We discovered that BRCA1 and GATA3 expressions were positively correlated in human breast cancer. Depletion of BRCA1 stimulated methylation of GATA3 promoter thereby repressing GATA3 transcription. We developed Brca1 and Gata3 deficient mouse system. We found that Gata3 deficiency in mice induced poorly-differentiated mammary tumors with the activation of EMT and promoted tumor initiating and metastatic potential. Gata3 deficient mammary tumors phenocopied Brca1 deficient tumors in the induction of EMT under the same genetic background. Reconstitution of Gata3 in Brca1-deficient tumor cells activated mesenchymal-epithelial transition, suppressing tumor initiation and metastasis. Conclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis. Ivyspring International Publisher 2021-07-13 /pmc/articles/PMC8344017/ /pubmed/34373738 http://dx.doi.org/10.7150/thno.59280 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Bai, Feng
Zhang, Li-Han
Liu, Xiong
Wang, Chuying
Zheng, Chenglong
Sun, Jianping
Li, Min
Zhu, Wei-Guo
Pei, Xin-Hai
GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer
title GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer
title_full GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer
title_fullStr GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer
title_full_unstemmed GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer
title_short GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer
title_sort gata3 functions downstream of brca1 to suppress emt in breast cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344017/
https://www.ncbi.nlm.nih.gov/pubmed/34373738
http://dx.doi.org/10.7150/thno.59280
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