Research Papers:
EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer
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Abstract
Xiaoping Wang1,2,3,*, Monica E. Reyes1,2,3,*, Dongwei Zhang1,2,3,*, Yohei Funakoshi1,2,3, Adriana P. Trape1,2,3, Yun Gong1,4, Takahiro Kogawa1,2,3, Bedrich L. Eckhardt1,2,3, Hiroko Masuda1,2,3, David A. Pirman Jr5, Peiying Yang6, James M. Reuben1,7, Wendy A. Woodward1,8, Chandra Bartholomeusz1,2,3, Gabriel N. Hortobagyi3, Debu Tripathy3 and Naoto T. Ueno1,2,3
1Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
5Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
6Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
7Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
8Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*These authors contributed equally to this work
Correspondence to:
Naoto T. Ueno, email: [email protected]
Xiaoping Wang, email: [email protected]
Keywords: inflammatory breast cancer, EGFR, COX-2, nodal, cancer stem-like cells
Received: October 19, 2016 Accepted: June 17, 2017 Published: July 04, 2017
ABSTRACT
Inflammatory breast cancer (IBC) is the most lethal and aggressive type of breast cancer, with a strong proclivity to metastasize, and IBC-specific targeted therapies have not yet been developed. Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in IBC. However, the mechanism behind the therapeutic effect of EGFR targeted therapy is not well defined. Here, we report that EGFR regulates the IBC cell population that expresses cancer stem-like cell (CSC) markers through COX-2, a key mediator of inflammation whose expression correlates with worse outcome in IBC. The COX-2 pathway promoted IBC cell migration and invasion and the CSC marker-bearing population in vitro, and the inhibition of this pathway reduced IBC tumor growth in vivo. Mechanistically, we identified Nodal, a member of the TGFβ superfamily, as a potential driver of COX-2-regulated invasive capacity and the CSC phenotype of IBC cells. Our data indicate that the EGFR pathway regulates the expression of COX-2, which in turn regulates the expression of Nodal and the activation of Nodal signaling. Together, our findings demonstrate a novel connection between the EGFR/COX-2/Nodal signaling axis and CSC regulation in IBC, which has potential implications for new combination approaches with EGFR targeted therapy for patients with IBC.
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PII: 18958