Abstract
In metastatic breast cancers, the acquisition of metastatic ability, which leads to clinically incurable disease and poor survival, has been associated with acquisition of epithelial-mesenchymal transition (EMT) program and self-renewing trait (CSCs) via activation of PI3K/AKT and IL6/JAK2/STAT3 signaling pathways. We found that TrkB is a key regulator of PI3K/AKT and JAK/STAT signal pathway-mediated tumor metastasis and EMT program. Here, we demonstrated that TrkB activates AKT by directly binding to c-Src, leading to increased proliferation. Also, TrkB increases Twist-1 and Twist-2 expression through activation of JAK2/STAT3 by inducing c-Src-JAK2 complex formation. Furthermore, TrkB in the absence of c-Src binds directly to JAK2 and inhibits SOCS3-mediated JAK2 degradation, resulting in increased total JAK2 and STAT3 levels, which subsequently leads to JAK2/STAT3 activation and Twist-1 upregulation. Additionally, activation of the JAK2/STAT3 pathway via induction of IL-6 secretion by TrkB enables induction of activation of the EMT program via induction of STAT3 nuclear translocation. These observations suggest that TrkB is a promising target for future intervention strategies to prevent tumor metastasis, EMT program and self-renewing trait in breast cancer.
Highlights
There are several discrete steps in the biological cascade of metastasis, loss of cellular adhesion, increased motility and invasiveness, entry and survival into circulation, exit into new tissue, and eventual colonization of a distant site [1, 2]
TrkB is overexpressed in several human cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, and its overexpression suppresses anoikis as an epithelial–mesenchymal transition (EMT) inducer by regulation of Zeb1 [23, 42]
Independent of these discoveries, CD44high/CD24low cells, which show a stem cell-like phenotype, are enriched in highly metastatic breast cancer cells have been proposed to be resistant to cancer therapies through activation of the PI3K/AKT pathway, IL-6/JAK2/STAT3 pathway, and EMT [8, 43,44,45,46,47]
Summary
There are several discrete steps in the biological cascade of metastasis, loss of cellular adhesion, increased motility and invasiveness, entry and survival into circulation, exit into new tissue, and eventual colonization of a distant site [1, 2]. Activation of the PI3K/ AKT pathway, IL-6/JAK2/STAT3 pathway, and stem cell-like characteristics contribute to the poor outcomes of metastatic breast cancers [8, 9]. Activated JAK2/STAT3 increases AKT activation through the induction of AKT [10], while increased STAT3 and AKT activation leads to tumor development and EMT [11, 12] Independent of these findings, TrkB, a member of the tropomyosin-related kinase (Trk) family of neurotrophin receptors, is critical to biological processes in the developing and mature nervous systems, including neuronal growth, differentiation, and survival [13]. We found that TrkB is primarily present in human breast cancer and acts as a key regulator of the PI3K/AKT and JAK/STAT signal pathway-mediated tumor metastasis, EMT, and selfrenewing trait
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