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

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

doi:10.18632/oncotarget.18958

Bedrich L. Eckhardt, Peiying Yang + Show 15 more

Open Access

https://doi.org/10.18632/oncotarget.18958

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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.

Highlights

Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer; it accounts for 2–4% of breast cancer cases but causes 8–10% of breast cancer-related deaths in the United States [1, 2].IBC tumors have features associated with poor prognosis, such as overexpression of HER2, Epidermal growth factor receptor (EGFR), E-cadherin, and nuclear factor κB [3]
These results indicate that the EGFR pathway regulates the cancer stem-like cell (CSC) marker-bearing population in IBC cells
We have shown that 1) the EGFR pathway regulates the expression of COX-2, a key molecule in the inflammatory response whose expression correlates with worse outcome of IBC patients and whose inhibition reduces IBC cells’ invasion and tumor growth; 2) both the EGFR and COX-2 pathways contribute to the regulation of IBC stemness; and 3) Nodal, a molecule involved in the regulation of stem cell pluripotency, is a key component in EGFR/COX-2mediated CSC regulation in IBC, and both the EGFR and COX-2 pathways regulate Nodal signaling

Summary

Introduction

IBC tumors have features associated with poor prognosis, such as overexpression of HER2, EGFR, E-cadherin, and nuclear factor κB [3]. There are no FDA-approved targeted therapies that are specific for IBC. IBC, including loss of WNT1-inducible signaling pathway protein-3 (WISP3) and overexpression of Rho GTPase [6], E-cadherin [7], angiogenic factors [8], translation initiation factor eIF4GI [9], and tazarotene-induced gene 1 (TIG1) [10]. The molecular mechanism underlying aggressiveness of IBC is not well understood. One proposed mechanism contributing to the aggressiveness of IBC is enrichment for cancer stem-like cells (CSCs). It has been shown that the metastatic, aggressive behavior of IBC is mediated by a CSC component that displays aldehyde dehydrogenase 1 (ALDH1) enzymatic activity [11].

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