TrkA interacts with and phosphorylates STAT3 to enhance gene transcription and promote breast cancer stem cells in triple-negative and HER2-enriched breast cancers
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
Date
2021-05-02Journal
CancersPublisher
MDPI AGType
Article
Metadata
Show full item recordAbstract
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-en-riched breast cancer, as shown by immunohistochemical staining and data mining. Through immu-nofluorescence 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 phosphor-ylation 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. © 2021 by the authors.Sponsors
U.S. Department of DefenseIdentifier to cite or link to this item
http://hdl.handle.net/10713/15716ae974a485f413a2113503eed53cd6c53
10.3390/cancers13102340