Oncotarget

Research Papers:

EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer

Xiaoping Wang, Monica E. Reyes, Dongwei Zhang, Yohei Funakoshi, Adriana P. Trape, Yun Gong, Takahiro Kogawa, Bedrich L. Eckhardt, Hiroko Masuda, David A. Pirman Jr, Peiying Yang, James M. Reuben, Wendy A. Woodward, Chandra Bartholomeusz, Gabriel N. Hortobagyi, Debu Tripathy and Naoto T. Ueno _

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Oncotarget. 2017; 8:67904-67917. https://doi.org/10.18632/oncotarget.18958

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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: nueno@mdanderson.org

Xiaoping Wang, email: xiwang@mdanderson.org

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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