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Oncotarget. 2017 Jul 4;8(40):67904-67917. doi: 10.18632/oncotarget.18958. eCollection 2017 Sep 15.

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

Author information

1
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
3
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
5
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
6
Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
7
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
8
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
#
Contributed equally

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.

KEYWORDS:

COX-2; EGFR; cancer stem-like cells; inflammatory breast cancer; nodal

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