Abstract 569: Targeting inflammatory pathways as an effective therapeutic approach to suppress tumorigenicity and prevent metastasis in inflammatory breast cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Inflammatory breast cancer (IBC) is a rare and aggressive type of advanced breast cancer with a poor long-term outcome and a high risk of recurrence. Although one of the most common clinical manifestations of IBC is erythema of the skin overlying the breast, whether inflammation is involved in IBC has not yet been tested by pathologic examination of IBC specimens. Therefore, whether inflammation pathways are involved in the pathogenesis of IBC is still not clear. A large body of evidence indicates that chronic inflammation is a risk factor for cancer. Nonsteroidal anti-inflammatory drugs have been reported to reduce the risk of developing some solid cancers, including breast cancer. Cyclooxygenase (COX)-2 is the inducible isoenzyme catalyzing the conversion of arachidonic acid to prostanoids. COX-2 upregulation has been linked to breast tumorigenesis or inflammatory diseases, and COX-2 overexpression increases the growth rate and invasiveness of breast cancer cells. We tested the hypothesis that the COX-2 pathway is involved in IBC tumor growth and metastasis. Methods and Results: We examined the expression level of COX-2 and the concentrations of its enzymatic products by mass spectrometry (LC/MS/MS). We also determined the effect of inhibition of the COX2 pathway on cell proliferation, migration, invasiveness, and epithelial-mesenchymal transition (EMT) in IBC both in vitro and in vivo. We found that levels of COX-2 and its enzymatic products prostaglandins (PG), such as PGE2 and PGF2α, were higher in IBC than in non-IBC cell lines. Both PGE2 and PGF2α markedly enhanced the migration and invasion of SUM149 IBC cells, suggesting that COX-2 and its metabolites may play an important role in IBC development and progression. We examined the expression levels of COX-2 and EGFR in 25 IBC patient biopsy samples and found that the expression of COX-2 was positively correlated with the levels of EGFR in these tissues. To illustrate how COX-2 and EGFR are regulated in IBC cells, we treated SUM149 cells with EGF. We found that EGF stimulation increased COX-2 levels. COX-2 expression was notably downregulated in EGFR shRNA stably transfected SUM149 cells, suggesting that the upregulation of COX-2 is mediated through EGFR signaling. Furthermore, a selective COX-2 inhibitor, celecoxib, dramatically inhibited IBC tumor growth in a SUM149 IBC xenograft model. These celecoxib-treated tumors exhibited high expression of the epithelial marker E-cadherin and low expression of the mesenchymal marker vimentin compared with untreated tumors, suggesting that celecoxib inhibits epithelial-mesenchymal transition. Conclusions: Our results suggest that inflammatory mediators indeed play an important role in IBC cells. Targeting inflammatory pathways may represent an effective therapeutic approach to suppress tumorigenicity and prevent metastasis in IBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 569. doi:1538-7445.AM2012-569