Abstract
Inflammatory breast cancer (IBC) is a rare but aggressive type of advanced breast cancer. Little is known about the etiology of IBC, and effective treatments for IBC are lacking. Recent clinical study showed that Epidermal growth factor receptor (EGFR) overexpression is detected in 30% of IBCs. EGFR-positive IBC is associated with significantly worse 5-year overall survival than EGFR-negative IBC, and EGFR expression is also associated with increased risk of IBC recurrence. In the present study, we determined the impact of blocking the EGFR pathway on IBC characteristics. Two IBC cell lines, SUM149 and KPL-4, which express high level of EGFR were studied. EGFR siRNA knockdown inhibited IBC cell proliferation. The EGFR tyrosine kinase inhibitor erlotinib inhibited proliferation and anchorage-independent growth of IBC cells, and this inhibition was ERK dependent. Erlotinib also inhibited cell motility and invasiveness. Furthermore, erlotinib reversed the mesenchymal phenotype of IBC cells, which may suggest more likely for metastasis, to epithelial phenotype in three-dimensional culture. More importantly, high doses of erlotinib showed significant tumor-growth inhibition in a xenograft model. Mean tumor-growth inhibition was 78% at 4 weeks after 50 mg/kg erlotinib treatment (P < 0.0001) and 95% after 100 mg/kg erlotinib treatment (P < 0.0001). Erlotinib also inhibited lung metastasis, even at a low dose (25 mg/kg). Metastatic tumors in lung were detected in 3 of 7 control mice but none of the 7 erlotinib-treated mice, indicating that erlotinib had activity to inhibit metastatsis of IBC (P < 0.05). Erlotinib-treated tumors had high expression of the epithelial marker E-cadherin and low expression of the mesenchymal marker vimentin compared with untreated tumors, suggesting that erlotinib exerts its antimetastatic activity in IBC by inhibiting epithelial-mesenchymal transition (EMT). Our results indicate that the EGFR pathway is involved in tumor growth and metastasis of IBC. Targeting EGFR through the ERK pathway may represent an effective therapeutic approach to EGFR-expressing IBC.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1767.
Footnotes
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
- American Association for Cancer Research