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

• Published in: Cancers Vol. 13; no. 10; p. 2340
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.05.2021; MDPI
• Subjects: Antibodies; Breast cancer; Cell growth; Chemotherapy; Confocal microscopy; Cytoplasm; ErbB-2 protein; Gene expression; Genes; Immunofluorescence; Immunoprecipitation; Janus kinase 2; Kinases; Ligands; Metastases; Metastasis; Myc protein; Nerve growth factor; Nuclear transport; Patients; Phosphorylation; Proteins; Signal transduction; Stat3 protein; Stem cells; Transcription activation; TrkA protein; Tumors; Western blotting; SOX2; breast cancer; TrkA; cancer stem cells; MYC; STAT3
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13102340

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, and . 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.