TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
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-overexpres...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/10/2340 |
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| author | Angelina T. Regua Noah R. Aguayo Sara Abu Jalboush Daniel L. Doheny Sara G. Manore Dongqin Zhu Grace L. Wong Austin Arrigo Calvin J. Wagner Yang Yu Alexandra Thomas Michael D. Chan Jimmy Ruiz Guangxu Jin Roy Strowd Peiqing Sun Jiayuh Lin Hui-Wen Lo |
| author_facet | Angelina T. Regua Noah R. Aguayo Sara Abu Jalboush Daniel L. Doheny Sara G. Manore Dongqin Zhu Grace L. Wong Austin Arrigo Calvin J. Wagner Yang Yu Alexandra Thomas Michael D. Chan Jimmy Ruiz Guangxu Jin Roy Strowd Peiqing Sun Jiayuh Lin Hui-Wen Lo |
| author_sort | Angelina T. Regua |
| collection | DOAJ |
| description | 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, <i>SOX2</i> and <i>MYC</i>. 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. |
| first_indexed | 2024-03-10T11:28:56Z |
| format | Article |
| id | doaj.art-94096733bb194533b356089812ff67d7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:28:56Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-94096733bb194533b356089812ff67d72023-11-21T19:24:31ZengMDPI AGCancers2072-66942021-05-011310234010.3390/cancers13102340TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast CancersAngelina T. Regua0Noah R. Aguayo1Sara Abu Jalboush2Daniel L. Doheny3Sara G. Manore4Dongqin Zhu5Grace L. Wong6Austin Arrigo7Calvin J. Wagner8Yang Yu9Alexandra Thomas10Michael D. Chan11Jimmy Ruiz12Guangxu Jin13Roy Strowd14Peiqing Sun15Jiayuh Lin16Hui-Wen Lo17Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USAWake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USAWake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USADepartment of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USAJAK2–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, <i>SOX2</i> and <i>MYC</i>. 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.https://www.mdpi.com/2072-6694/13/10/2340breast cancerTrkASTAT3cancer stem cellsSOX2MYC |
| spellingShingle | Angelina T. Regua Noah R. Aguayo Sara Abu Jalboush Daniel L. Doheny Sara G. Manore Dongqin Zhu Grace L. Wong Austin Arrigo Calvin J. Wagner Yang Yu Alexandra Thomas Michael D. Chan Jimmy Ruiz Guangxu Jin Roy Strowd Peiqing Sun Jiayuh Lin Hui-Wen Lo TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers Cancers breast cancer TrkA STAT3 cancer stem cells SOX2 MYC |
| 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 | breast cancer TrkA STAT3 cancer stem cells SOX2 MYC |
| url | https://www.mdpi.com/2072-6694/13/10/2340 |
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