• 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; et al. (MDPI AG, 2021-05-02)
      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.