Abstract 5443: FOXC1 is a critical mediator of EGFR function in basal-like breast cancer.
Authors: Yanli Jin, Bingchen Han, Wolf Ruprecht Wiedemeyer, Sandra Orsulic, Beth Karlan, Armando Giuliano, Xiaojiang Cui
Journal: Cancer Research (2013)

Abstract Basal-like breast cancer (BLBC) is an aggressive malignancy that is associated with high histological grade, aggressive clinical behavior, a high rate of metastasis to the lung and brain, and poor prognosis. Currently, chemotherapy is the only systemic therapy for BLBC, which underexpresses estrogen receptor (ER), progesterone receptor (PR), and HER2. To date, little is known about the molecular basis of BLBC. We and others recently reported that the forkhead box C1 (FOXC1) transcription factor is a critical maker for BLBC and predicts poor clinical outcome in human breast cancer. Overexpression of FOXC1 increases BLBC cell growth, migration, invasion, epithelial-mesenchymal transition, and chemoresistance. However, how its expression is induced exclusively in BLBC is not understood. Previous studies have shown that EGFR is overexpressed in BLBC and is associated with poor prognosis in breast cancer patients. We thus hypothesize that activated EGFR signaling may regulate FOXC1 expression. In this study, we show that EGF treatment upregulates FOXC1 expression in BLBC cells at the transcription level through MEKK1/ERK and PI3K/AKT pathways. AKT3, which was recently found to be enriched in ER/PR/HER2 triple-negative breast cancer, is a potent activator of FOXC1 transcription. Overexpression of EGFRvIII, a truncated constitutively active form of EGFR that does not bind to the ligand, also induced FOXC1 expression. Pharmacologic inhibition of EGFR suppressed FOXC1 expression in BLBC cells. Immunohistochemistry and microarray analysis demonstrated that FOXC1 expression was positively, significantly correlated with EGFR expression in human BLBC tumors at protein and RNA levels. Moreover, we identified the nuclear factor κB (NF-κB) transcription factor as a pivotal regulator of EGF-induced FOXC1 expression, downstream of AKT and ERK. NF-κB directly activates FOXC1 transcription through binding to the FOXC1 promoter. Deletion or mutation of the NF-κB binding sites in the FOXC1 promoter abolished the EGF induction of FOXC1 expression. Knockdown of FOXC1 levels in BLBC cells by RNA interference markedly attenuated EGF-elicited cell proliferation, migration and invasion, suggesting that FOXC1 mediates the effects of EGF on BLBC cell functions. Taken together, our findings uncovered a novel mechanism of FOXC1 regulation and shed light on the role of EGFR-NF-κB-FOXC1 signaling in BLBC pathogenesis. Intervention of this signaling pathway would provide potential modalities for BLBC treatment. FOXC1 levels may serve as a readout of EGFR activity and a marker for selecting breast cancer patients who may benefit from anti-EGFR therapy. Citation Format: Yanli Jin, Bingchen Han, Wolf Ruprecht Wiedemeyer, Sandra Orsulic, Beth Karlan, Armando Giuliano, Xiaojiang Cui. FOXC1 is a critical mediator of EGFR function in basal-like breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5443. doi:10.1158/1538-7445.AM2013-5443