Inflammatory breast cancer (IBC) is a rare but very aggressive type of advanced breast cancer that accounts for 1% to 5% of all breast cancer cases in the United States (1
). IBC can initially present as either stage IIIB locally advanced or stage IV breast cancer (3
). IBC is characterized by extensive lymphovascular invasion and is associated with a high risk of distant metastases (4
). Even when treated with multimodality strategies including chemotherapy, surgery, and radiation therapy, IBC is associated with a poor long-term outcome and a high risk of recurrence and metastasis compared with non-inflammatory locally advanced breast cancer. The 3-year survival rate among IBC patients is only about 40%, much lower than the 85% 3-year survival rate among patients with non-inflammatory breast cancer (5
). To date, effective standard therapies for IBC are limited. Therefore, novel therapeutic approaches need to be developed. Studying the biological basis of IBC will allow us to develop novel targeted therapies to improve the outcome of IBC.
It is reported that up to 30% of IBC patients have distant metastases at the time of diagnosis, in contrast to 5% of patients with non-inflammatory breast cancer (6
). The lower survival rate of patients with IBC is thought to be due to the highly metastatic nature of the disease. An important event during malignant tumor progression and metastasis is epithelial-mesenchymal transition (EMT), a process by which cells undergo a morphological switch from a polarized epithelial phenotype to a mesenchymal fibroblastoid phenotype (7
). EMT is characterized by the loss of epithelial markers (E-cadherin, cytokeratins) and the presence of mesenchymal markers (vimentin, fibronectin). Evidence of the importance of EMT in metastasis includes the fact that reduction of E-cadherin may contribute to metastatic spread of breast cancer (10
The epidermal growth factor receptor (EGFR/ErbB1) and HER2 (ErbB2), members of the ErbB receptor tyrosine kinase family, are frequently overexpressed in human malignant tumors and are known to drive tumor growth and progression (11
). Stimulation of EGFR is associated with cell proliferation and with multiple processes involved in tumor progression, invasion, and metastasis (16
). Overexpression of EGFR is associated with poor prognosis and reduced overall survival in patients with lung cancer (18
). Therefore, the EGFR signaling pathway has emerged as a promising target for cancer therapy. A number of EGFR tyrosine kinase inhibitors (TKIs) that target EGFR have been developed and used successfully to treat cancer patients. For example, erlotinib, a small-molecule EGFR TKI, is used to treat non-small cell lung cancer, pancreatic cancer, and several other types of cancer (21
). However, in non-inflammatory breast cancer, EGFR TKIs such as erlotinib and gefitinib have shown minimum clinical activity (23
). Further, when the activity of an EGFR/HER2 dual tyrosine kinase inhibitor, lapatinib, was tested in IBC, lapatinib exhibited clinical activity only in heavily pretreated HER2-positive IBC (25
In our previous study, we showed that EGFR overexpression was detected in 30% of IBC patients by immunohistochemical staining. EGFR-expressing IBC was associated with a significantly worse 5-year overall survival rate than EGFR-negative IBC, and EGFR expression was associated with increased risk of IBC recurrence (26
). Thus, EGFR may represent a potential therapeutic target in IBC. However, the biological association between EGFR expression and poor prognosis and increased risk of recurrence is not known in IBC, and the impact of EGFR TKIs on metastasis of IBC has not been evaluated.
In the study reported here, we found that erlotinib exhibits ERK-dependent antiproliferative activity in IBC. Furthermore, erlotinib reversed the mesenchymal phenotype of IBC cells to epithelial phenotype in 3-dimensional (3D) culture. More importantly, erlotinib inhibited the tumor growth and spontaneous lung metastasis of IBC in an orthotopic IBC xenograft model. Our study provides a rationale for developing novel treatment strategies targeting the EGFR and ERK pathways to inhibit the growth and metastasis of EGFR-expressing IBC.