Signal Transduction
Epithelial to Mesenchymal Transition Promotes Breast Cancer Progression via a Fibronectin-dependent STAT3 Signaling Pathway*

https://doi.org/10.1074/jbc.M113.475277Get rights and content
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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 β1 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.

Background:

Cells perceive their environment through soluble growth factors and in response to extracellular matrix.

Results:

STAT3 signaling can be activated by multiple pathways during breast cancer progression.

Conclusion:

Fibronectin:STAT3 signaling promotes three-dimensional outgrowth of breast cancer cells.

Significance:

This study demonstrates a novel mechanism by which STAT3 becomes activated by the extracellular matrix independent of the canonical EGF receptor signaling network.

Breast Cancer
Epidermal Growth Factor Receptor (EGFR)
Epithelial to Mesenchymal Transition
Fibronectin
Integrin
STAT3
JAK2

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*

This work was supported, in whole or in part, by National Institutes of Health Grants GM081498 (to C. R. C.), CA129359 (to W. P. S.), CA166140 (to M. K. W.), and T32 HL007653 (to N. B.), and pilot project Grant CA043703 from development funds of the Case Comprehensive Cancer Center Support (to C. R. C. and Z. W.).

1

Both authors contributed equally to this work.