title: Epithelial to mesenchymal transition promotes breast cancer progression via a fibronectin-dependent STAT3 signaling pathway.
abstract: 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.
authors: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: Nikolas
authors: N
authors: Balanis
authors: Michael K
authors: MK
authors: Wendt
authors: Barbara J
authors: BJ
authors: Schiemann
authors: Zhenghe
authors: Z
authors: Wang
authors: William P
authors: WP
authors: Schiemann
authors: Cathleen R
authors: CR
authors: Carlin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D005353:Fibronectins; D050796:STAT3 Transcription Factor; D053773:Transforming Growth Factor beta1; C512478:EGFR protein, human; D066246:ErbB Receptors; D051418:Focal Adhesion Kinase 2; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Breast Cancer; Epidermal Growth Factor Receptor (EGFR); Epithelial to Mesenchymal Transition; Fibronectin; Integrin; JAK2; STAT3
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