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Epithelial to mesenchymal transition promotes breast cancer progression via a
fibronectin-dependent STAT3 signaling pathway
#MMPMID23653350
Balanis N
; Wendt MK
; Schiemann BJ
; Wang Z
; Schiemann WP
; Carlin CR
J Biol Chem
2013[Jun]; 288
(25
): 17954-67
PMID23653350
show ga
We previously established that overexpression of the EGF receptor (EGFR) is
sufficient to induce tumor formation by otherwise nontransformed mammary
epithelial cells, and that the initiation of epithelial-mesenchymal transition
(EMT) is capable of increasing the invasion and metastasis of these cells. Using
this breast cancer (BC) model, we find that in addition to EGF, adhesion to
fibronectin (FN) activates signal transducer and activator of transcription 3
(STAT3) through EGFR-dependent and -independent mechanisms. Importantly, EMT
facilitated a signaling switch from SRC-dependent EGFR:STAT3 signaling in pre-EMT
cells to EGFR-independent FN:JAK2:STAT3 signaling in their post-EMT counterparts,
thereby sensitizing these cells to JAK2 inhibition. Accordingly, human metastatic
BC cells that failed to activate STAT3 downstream of EGFR did display robust
STAT3 activity upon adhesion to FN. Furthermore, FN enhanced outgrowth in
three-dimensional organotypic cultures via a mechanism that is dependent upon ?1
integrin, Janus kinase 2 (JAK2), and STAT3 but not EGFR. Collectively, our data
demonstrate that matrix-initiated signaling is sufficient to drive STAT3
activation, a reaction that is facilitated by EMT during BC metastatic
progression.
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