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TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers

SIMPLE SUMMARY: Breast cancer is the leading cancer in American women. Due to the inherent aggressiveness of triple-negative and HER2-enriched breast cancers, it is imperative to identify novel molecular targets for therapeutic intervention. Due to their abnormal activities in metastatic breast canc...

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Autores principales: Regua, Angelina T., Aguayo, Noah R., Jalboush, Sara Abu, Doheny, Daniel L., Manore, Sara G., Zhu, Dongqin, Wong, Grace L., Arrigo, Austin, Wagner, Calvin J., Yu, Yang, Thomas, Alexandra, Chan, Michael D., Ruiz, Jimmy, Jin, Guangxu, Strowd, Roy, Sun, Peiqing, Lin, Jiayuh, Lo, Hui-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150921/
https://www.ncbi.nlm.nih.gov/pubmed/34066153
http://dx.doi.org/10.3390/cancers13102340
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author Regua, Angelina T.
Aguayo, Noah R.
Jalboush, Sara Abu
Doheny, Daniel L.
Manore, Sara G.
Zhu, Dongqin
Wong, Grace L.
Arrigo, Austin
Wagner, Calvin J.
Yu, Yang
Thomas, Alexandra
Chan, Michael D.
Ruiz, Jimmy
Jin, Guangxu
Strowd, Roy
Sun, Peiqing
Lin, Jiayuh
Lo, Hui-Wen
author_facet Regua, Angelina T.
Aguayo, Noah R.
Jalboush, Sara Abu
Doheny, Daniel L.
Manore, Sara G.
Zhu, Dongqin
Wong, Grace L.
Arrigo, Austin
Wagner, Calvin J.
Yu, Yang
Thomas, Alexandra
Chan, Michael D.
Ruiz, Jimmy
Jin, Guangxu
Strowd, Roy
Sun, Peiqing
Lin, Jiayuh
Lo, Hui-Wen
author_sort Regua, Angelina T.
collection PubMed
description SIMPLE SUMMARY: Breast cancer is the leading cancer in American women. Due to the inherent aggressiveness of triple-negative and HER2-enriched breast cancers, it is imperative to identify novel molecular targets for therapeutic intervention. Due to their abnormal activities in metastatic breast cancers, JAK2–STAT3 and TrkA pathways have been individually implicated in aggressive breast tumors. However, their co-activation and signaling interactions have not been thoroughly investigated. Therefore, our study aimed to elucidate the extent of crosstalk between JAK2–STAT3 and TrkA signaling pathways and its impact on breast cancer. Our data revealed a novel interaction between TrkA and STAT3, and that this interaction results in STAT3 phosphorylation and activation by TrkA, leading to enhanced stemness gene expression and stem cell renewal. We further found that the co-activation of JAK2–STAT3 and TrkA pathways is correlated with shorter time to develop overall and organ-specific metastasis, suggesting that this signaling crosstalk underlies the aggressiveness of triple-negative and HER2-enriched breast cancers. ABSTRACT: JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.
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spelling pubmed-81509212021-05-27 TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers Regua, Angelina T. Aguayo, Noah R. Jalboush, Sara Abu Doheny, Daniel L. Manore, Sara G. Zhu, Dongqin Wong, Grace L. Arrigo, Austin Wagner, Calvin J. Yu, Yang Thomas, Alexandra Chan, Michael D. Ruiz, Jimmy Jin, Guangxu Strowd, Roy Sun, Peiqing Lin, Jiayuh Lo, Hui-Wen Cancers (Basel) Article SIMPLE SUMMARY: Breast cancer is the leading cancer in American women. Due to the inherent aggressiveness of triple-negative and HER2-enriched breast cancers, it is imperative to identify novel molecular targets for therapeutic intervention. Due to their abnormal activities in metastatic breast cancers, JAK2–STAT3 and TrkA pathways have been individually implicated in aggressive breast tumors. However, their co-activation and signaling interactions have not been thoroughly investigated. Therefore, our study aimed to elucidate the extent of crosstalk between JAK2–STAT3 and TrkA signaling pathways and its impact on breast cancer. Our data revealed a novel interaction between TrkA and STAT3, and that this interaction results in STAT3 phosphorylation and activation by TrkA, leading to enhanced stemness gene expression and stem cell renewal. We further found that the co-activation of JAK2–STAT3 and TrkA pathways is correlated with shorter time to develop overall and organ-specific metastasis, suggesting that this signaling crosstalk underlies the aggressiveness of triple-negative and HER2-enriched breast cancers. ABSTRACT: JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer. MDPI 2021-05-12 /pmc/articles/PMC8150921/ /pubmed/34066153 http://dx.doi.org/10.3390/cancers13102340 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Regua, Angelina T.
Aguayo, Noah R.
Jalboush, Sara Abu
Doheny, Daniel L.
Manore, Sara G.
Zhu, Dongqin
Wong, Grace L.
Arrigo, Austin
Wagner, Calvin J.
Yu, Yang
Thomas, Alexandra
Chan, Michael D.
Ruiz, Jimmy
Jin, Guangxu
Strowd, Roy
Sun, Peiqing
Lin, Jiayuh
Lo, Hui-Wen
TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
title TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
title_full TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
title_fullStr TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
title_full_unstemmed TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
title_short TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
title_sort trka interacts with and phosphorylates stat3 to enhance gene transcription and promote breast cancer stem cells in triple-negative and her2-enriched breast cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150921/
https://www.ncbi.nlm.nih.gov/pubmed/34066153
http://dx.doi.org/10.3390/cancers13102340
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