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

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.

<p>Biomarkers for Inflammatory Breast Cancer: Diagnostic and Therapeutic Utility</p>

“…61 Upregulation of COX2 and subsequently prostaglandin E2 (PGE2) overexpression is a result of chronic inflammation in TME. 62 Table 1 reviews molecular biomarkers in IBC.…”

Decorin, a novel negative modulator of E-cadherin in inflammatory breast cancer

“…Major efforts have been undertaken to elucidate IBC tumor biology and to identify molecular alterations distinct to IBC that potentially might be translated into novel therapeutic strategies. Several important targets and pathways have been identified, including overexpression of EGFR, 5 overexpression of IFITM1, 6 RhoC, 7 E-cadherin, 8 XIAP, 9 TIG1 and Axl, 10 and eIFG4I, 11 and downregulation of TGFβ and WISP3, 7 as well as pathways associated with enrichment of the stem cell phenotype 12,13 and angiogenesis. 8 These efforts have significantly contributed to our understanding of IBC; however, the molecular basis for the unique and aggressive biology of IBC is still not well understood, and effective targeted therapies for this disease remain limited.…”

Kanser Geli̇şi̇mi̇nde İnflamasyonun Rolü

“…Bununla birlikte, CCL28'in aşırı ekspresyonu, metastaza bağlı protein matriks metalloproteinaz MMP2 ve MMP9 ve VEGF'nin ekspresyonunu etkilememiştir. Hayvan modellerinden alınan doku örneği analizleri, meme karsinomalarında CCL28'in aşırı ekspresyonunun artmış pERK ekspresyonu ve azaltılmış β-katenin ifadesi ile ilişkili olduğunu göstermiştir [72].…”