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Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to impro...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357760/ https://www.ncbi.nlm.nih.gov/pubmed/34241740 http://dx.doi.org/10.1007/s10549-021-06316-2 |
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author | Park, Jihyun Tacam, Moises J. Chauhan, Gaurav Cohen, Evan N. Gagliardi, Maria Iles, Lakesla R. Ueno, Naoto T. Battula, Venkata L. Sohn, Yoo-Kyoung Wang, Xiaoping Kim, Hak-Sung Krishnamurthy, Savitri Fowlkes, Natalie W. Green, Morgan M. Bartholomeusz, Geoffrey A. Tripathy, Debu Reuben, James M. Bartholomeusz, Chandra |
author_facet | Park, Jihyun Tacam, Moises J. Chauhan, Gaurav Cohen, Evan N. Gagliardi, Maria Iles, Lakesla R. Ueno, Naoto T. Battula, Venkata L. Sohn, Yoo-Kyoung Wang, Xiaoping Kim, Hak-Sung Krishnamurthy, Savitri Fowlkes, Natalie W. Green, Morgan M. Bartholomeusz, Geoffrey A. Tripathy, Debu Reuben, James M. Bartholomeusz, Chandra |
author_sort | Park, Jihyun |
collection | PubMed |
description | BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to improving patient outcomes. Developing targeted gene therapy is thus a high priority for TNBC patients. PEA15 (phosphoprotein enriched in astrocytes, 15 kDa) is known to bind to ERK, preventing ERK from being translocated to the nucleus and hence blocking its activity. The biological function of PEA15 is tightly regulated by its phosphorylation at Ser104 and Ser116. However, the function and impact of phosphorylation status of PEA15 in the regulation of TNBC metastasis and in epithelial-to-mesenchymal transition (EMT) are not well understood. METHODS: We established stable cell lines overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEA15-DD) mutants. To dissect specific cellular mechanisms regulated by PEA15 phosphorylation status, we performed RT-PCR immune and metastasis arrays. In vivo mouse models were used to determine the effects of PEA15 phosphorylation on tumor growth and metastasis. RESULTS: We found that the nonphosphorylatable mutant PEA15-AA prevented formation of mammospheres and expression of EMT markers in vitro and decreased tumor growth and lung metastasis in in vivo experiments when compared to control, PEA15-WT and phosphomimetic PEA15-DD. However, phosphomimetic mutant PEA15-DD promoted migration, mesenchymal marker expression, tumorigenesis, and lung metastasis in the mouse model. PEA15-AA-mediated inhibition of breast cancer cell migratory capacity and tumorigenesis was the partial result of decreased expression of interleukin-8 (IL-8). Further, we identified that expression of IL-8 was possibly mediated through one of the ERK downstream molecules, Ets-1. CONCLUSIONS: Our results show that PEA15 phosphorylation status serves as an important regulator for PEA15’s dual role as an oncogene or tumor suppressor and support the potential of PEA15-AA as a therapeutic strategy for treatment of TNBC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10549-021-06316-2. |
format | Online Article Text |
id | pubmed-8357760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-83577602021-08-30 Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression Park, Jihyun Tacam, Moises J. Chauhan, Gaurav Cohen, Evan N. Gagliardi, Maria Iles, Lakesla R. Ueno, Naoto T. Battula, Venkata L. Sohn, Yoo-Kyoung Wang, Xiaoping Kim, Hak-Sung Krishnamurthy, Savitri Fowlkes, Natalie W. Green, Morgan M. Bartholomeusz, Geoffrey A. Tripathy, Debu Reuben, James M. Bartholomeusz, Chandra Breast Cancer Res Treat Preclinical Study BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to improving patient outcomes. Developing targeted gene therapy is thus a high priority for TNBC patients. PEA15 (phosphoprotein enriched in astrocytes, 15 kDa) is known to bind to ERK, preventing ERK from being translocated to the nucleus and hence blocking its activity. The biological function of PEA15 is tightly regulated by its phosphorylation at Ser104 and Ser116. However, the function and impact of phosphorylation status of PEA15 in the regulation of TNBC metastasis and in epithelial-to-mesenchymal transition (EMT) are not well understood. METHODS: We established stable cell lines overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEA15-DD) mutants. To dissect specific cellular mechanisms regulated by PEA15 phosphorylation status, we performed RT-PCR immune and metastasis arrays. In vivo mouse models were used to determine the effects of PEA15 phosphorylation on tumor growth and metastasis. RESULTS: We found that the nonphosphorylatable mutant PEA15-AA prevented formation of mammospheres and expression of EMT markers in vitro and decreased tumor growth and lung metastasis in in vivo experiments when compared to control, PEA15-WT and phosphomimetic PEA15-DD. However, phosphomimetic mutant PEA15-DD promoted migration, mesenchymal marker expression, tumorigenesis, and lung metastasis in the mouse model. PEA15-AA-mediated inhibition of breast cancer cell migratory capacity and tumorigenesis was the partial result of decreased expression of interleukin-8 (IL-8). Further, we identified that expression of IL-8 was possibly mediated through one of the ERK downstream molecules, Ets-1. CONCLUSIONS: Our results show that PEA15 phosphorylation status serves as an important regulator for PEA15’s dual role as an oncogene or tumor suppressor and support the potential of PEA15-AA as a therapeutic strategy for treatment of TNBC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10549-021-06316-2. Springer US 2021-07-09 2021 /pmc/articles/PMC8357760/ /pubmed/34241740 http://dx.doi.org/10.1007/s10549-021-06316-2 Text en © The Author(s) 2021 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/) . |
spellingShingle | Preclinical Study Park, Jihyun Tacam, Moises J. Chauhan, Gaurav Cohen, Evan N. Gagliardi, Maria Iles, Lakesla R. Ueno, Naoto T. Battula, Venkata L. Sohn, Yoo-Kyoung Wang, Xiaoping Kim, Hak-Sung Krishnamurthy, Savitri Fowlkes, Natalie W. Green, Morgan M. Bartholomeusz, Geoffrey A. Tripathy, Debu Reuben, James M. Bartholomeusz, Chandra Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression |
title | Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression |
title_full | Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression |
title_fullStr | Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression |
title_full_unstemmed | Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression |
title_short | Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression |
title_sort | nonphosphorylatable pea15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of il-8 expression |
topic | Preclinical Study |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357760/ https://www.ncbi.nlm.nih.gov/pubmed/34241740 http://dx.doi.org/10.1007/s10549-021-06316-2 |
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