BACKGROUND: Human basal-like breast cancer (BLBC) has a poor prognosis and is often identified by expression of the epidermal growth factor receptor (EGFR). BLBC remains a major clinical challenge because its pathogenesis is not well understood, thus hindering efforts to develop targeted therapies. Recent data implicate the forkhead box C1 (FOXC1) transcription factor as an important prognostic biomarker and functional regulator of BLBC, but its regulatory mechanism and impact on BLBC tumorigenesis remain unclear. METHODS: The association between FOXC1 and EGFR expression in human breast cancer was examined by immunohistochemistry in formalin-fixed tissues and analysis of the TCGA database. The regulation of FOXC1 by EGFR activation was investigated in MDA-MB-468 cells using immunoblotting, qRT-PCR, and luciferase activity assays. This EGFR effect on FOXC1 expression was confirmed using the MDA-MB-468 xenograft model. RESULTS: Both FOXC1 mRNA and protein levels significantly correlated with EGFR expression in human breast tumors. EGFR activation induced FOXC1 transcription through the ERK and Akt pathways in BLBC. EGFR inhibition in vivo reduced FOXC1 expression in xenograft tumors. We also found that FOXC1 knockdown impaired the effects of EGF on BLBC cell proliferation, migration, and invasion. CONCLUSIONS: Our findings uncover a novel EGFR-FOXC1 signaling axis critical for BLBC cell functions, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.
BACKGROUND:Human basal-like breast cancer (BLBC) has a poor prognosis and is often identified by expression of the epidermal growth factor receptor (EGFR). BLBC remains a major clinical challenge because its pathogenesis is not well understood, thus hindering efforts to develop targeted therapies. Recent data implicate the forkhead box C1 (FOXC1) transcription factor as an important prognostic biomarker and functional regulator of BLBC, but its regulatory mechanism and impact on BLBC tumorigenesis remain unclear. METHODS: The association between FOXC1 and EGFR expression in humanbreast cancer was examined by immunohistochemistry in formalin-fixed tissues and analysis of the TCGA database. The regulation of FOXC1 by EGFR activation was investigated in MDA-MB-468 cells using immunoblotting, qRT-PCR, and luciferase activity assays. This EGFR effect on FOXC1 expression was confirmed using the MDA-MB-468 xenograft model. RESULTS: Both FOXC1 mRNA and protein levels significantly correlated with EGFR expression in humanbreast tumors. EGFR activation induced FOXC1 transcription through the ERK and Akt pathways in BLBC. EGFR inhibition in vivo reduced FOXC1 expression in xenograft tumors. We also found that FOXC1 knockdown impaired the effects of EGF on BLBC cell proliferation, migration, and invasion. CONCLUSIONS: Our findings uncover a novel EGFR-FOXC1 signaling axis critical for BLBC cell functions, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.
Authors: Shantanu Banerji; Kristian Cibulskis; Claudia Rangel-Escareno; Kristin K Brown; Scott L Carter; Abbie M Frederick; Michael S Lawrence; Andrey Y Sivachenko; Carrie Sougnez; Lihua Zou; Maria L Cortes; Juan C Fernandez-Lopez; Shouyong Peng; Kristin G Ardlie; Daniel Auclair; Veronica Bautista-Piña; Fujiko Duke; Joshua Francis; Joonil Jung; Antonio Maffuz-Aziz; Robert C Onofrio; Melissa Parkin; Nam H Pho; Valeria Quintanar-Jurado; Alex H Ramos; Rosa Rebollar-Vega; Sergio Rodriguez-Cuevas; Sandra L Romero-Cordoba; Steven E Schumacher; Nicolas Stransky; Kristin M Thompson; Laura Uribe-Figueroa; Jose Baselga; Rameen Beroukhim; Kornelia Polyak; Dennis C Sgroi; Andrea L Richardson; Gerardo Jimenez-Sanchez; Eric S Lander; Stacey B Gabriel; Levi A Garraway; Todd R Golub; Jorge Melendez-Zajgla; Alex Toker; Gad Getz; Alfredo Hidalgo-Miranda; Matthew Meyerson Journal: Nature Date: 2012-06-20 Impact factor: 49.962
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Authors: Aslaug Aa Muggerud; Jo Anders Rønneberg; Fredrik Wärnberg; Johan Botling; Florence Busato; Jovana Jovanovic; Hiroko Solvang; Ida Bukholm; Anne-Lise Børresen-Dale; Vessela N Kristensen; Therese Sørlie; Jörg Tost Journal: Breast Cancer Res Date: 2010-01-07 Impact factor: 6.466