Persistent activation of STAT3 by PIM2‐driven positive feedback loop for epithelial‐mesenchymal transition in breast cancer

Metastasis of breast cancer is promoted by epithelial–mesenchymal transition (EMT). Emerging evidence suggests that STAT3 is a critical signaling node in EMT and is constitutively activated in many carcinomas, including breast cancer. However, its signaling mechanisms underlying persistent activatio...

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Bibliographic Details
Published in:Cancer science 2015-06, Vol.106 (6), p.718-725
Main Authors: Uddin, Nizam, Kim, Rae‐Kwon, Yoo, Ki‐Chun, Kim, Young‐Heon, Cui, Yan‐Hong, Kim, In‐Gyu, Suh, Yongjoon, Lee, Su‐Jae
Format: Article
Language:English
Subjects:
Breast cancer
Breast carcinoma
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Movement
Cytokines
Epithelial-Mesenchymal Transition
Feedback
Female
Growth factors
Homeodomain Proteins - physiology
Humans
Interleukin-1alpha - metabolism
Interleukin-8 - metabolism
Invasiveness
Kinases
Medical prognosis
Mesenchyme
Metastases
Metastasis
Neoplasm Invasiveness
Original
Penicillin
Phosphorylation
PIM2
Polyclonal antibodies
positive feedback loop
Protein Serine-Threonine Kinases - physiology
Proteins
Proto-Oncogene Proteins - physiology
Signal Transduction
STAT3
Stat3 protein
STAT3 Transcription Factor - physiology
Transcription factors
Transcription Factors - physiology
Tumors
Zinc Finger E-box-Binding Homeobox 1
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Summary:Metastasis of breast cancer is promoted by epithelial–mesenchymal transition (EMT). Emerging evidence suggests that STAT3 is a critical signaling node in EMT and is constitutively activated in many carcinomas, including breast cancer. However, its signaling mechanisms underlying persistent activation of STAT3 associated with EMT remain obscure. Here, we report that PIM2 promotes activation of STAT3 through induction of cytokines. Activation of STAT3 caused an increase in PIM2 expression, implicating a positive feedback loop between PIM2 and STAT3. In agreement, targeting of either PIM2, STAT3 or PIM2‐dependent cytokines suppressed EMT‐associated migratory and invasive properties through inhibition of ZEB1. Taken together, our findings identify the signaling mechanisms underlying the persistent activation of STAT3 and the oncogenic role of PIM2 in EMT in breast cancer. PIM2 promotes epithelial‐mesenchymal transition through activation of STAT3. PIM2 activates STAT3 through induction of IL‐8 in breast cancer cells. STAT3 is constitutively activated by PIM2‐driven positive feedback loop.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.12668