Abstract
Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer.
Highlights
Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and cancer stem cells (CSCs) status
Our previous studies have already demonstrated that TrkC plays a crucial role in initiation, progression, and metastasis of cancer by inducing activation of the PI3K-AKT cascade[32] and Twist-1 expression[33], TrkC expression patterns have not been well characterized in human breast cancer
We found that TrkC was sufficient for direct interaction with JAK2 and blocked SOCS3-induced JAK2 degradation, which resulted in stabilization of JAK2 expression and induction of STAT3, as well as the upregulation of Twist-1 gene expression
Summary
Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. Recent studies have identified several somatic mutations in TrkC implicated in breast (R678Q)[24,25], lung (V307L, H677Y, L336Q, R721F)[25,26], gastric (T149R)[25], colorectal (G608S, I695V, R731Q, K732T, L760I)[27], and pancreatic (G608S, E322K, H599Y)[28,29,30] cancers These results suggest that TrkC may have high mutation rates in human cancer genomes and can be potentially activated by somatic mutations. We recently demonstrated that c-Src activation by TrkC induces activation of the PI3K-AKT pathway[32] These findings indicate that TrkC activation/overexpression may play a crucial role in the initiation, progression, and metastasis of breast cancer and other tumors.
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