Abstract A17: Regulation of EGFR: Stat3 signaling by Mig6 is required for metastatic outgrowth in triple-negative breast cancer

Stat3 is an oncogene that enriches for tumor initiating breast cancer cells. Stat3 activity is driven by numerous signaling inputs, including those initiated by EGFR. Herein we shown that Stat3 is critically involved in EGFR-driven tumorigenesis as EGFR molecules harboring a mutation in the juxtamembrane domain that specifically prevents activation of Stat3 fail to transform mammary epithelial cells. Using this model of EGFR transformation, we previously established that the induction of epithelial-mesenchymal transition (EMT) enhances pulmonary tumor formation. Surprisingly, EMT drastically diminishes the capacity of EGFR to signal to Stat3. Indeed, using the MCF-10A progression series, we show that constitutive activation of Stat3 is consistent with the acquisition of a mesenchymal phenotype but independent of EGFR activity. As a compensatory mechanism, we find that EMT increases the expression and ability of fibronectin to directly activate Stat3 in an EGFR-independent, Jak2-dependent manor. Indeed, human triple-negative breast cancer (TNBC) cells that fail to activate Stat3 in response to EGF robustly activate Stat3 upon fibronectin adhesion. Consistent with these results, TNBC outgrowth in pulmonary 3D-organotypic cultures is enhanced by the addition of fibronectin, a process that is absolutely dependent on β1-integrin, Jak2 and Stat3, but independent of EGFR. Underscoring the importance of this switch from EGFR-mediated to fibronectin-mediated Stat3 activation in metastatic TNBC cells, we demonstrate that shRNA-mediated diminution of the EGFR inhibitory molecule MIG6 results in increased apoptosis and consequently, decreased pulmonary tumor formation by TNBC cells. Our data clearly demonstrate that matrix-initiated signaling is sufficient to drive Stat3 activation, a reaction that likely contributes to the resistance of metastatic TNBCs to molecular therapies, particularly those that target EGFR. Citation Format: Mike K. Wendt, Nikolas Balanis, Barbara Schiemann, Cathleen Carlin, William Schiemann. Regulation of EGFR: Stat3 signaling by Mig6 is required for metastatic outgrowth in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A17.