title: FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer.
abstract: 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.
authors.affiliation: Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Jin
authors.forename: Bingchen
authors.initials: B
authors.lastname: Han
authors.forename: Jiongyu
authors.initials: J
authors.lastname: Chen
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Wiedemeyer
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
authors.forename: Shikha
authors.initials: S
authors.lastname: Bose
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Armando E
authors.initials: AE
authors.lastname: Giuliano
authors.forename: Yukun
authors.initials: Y
authors.lastname: Cui
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077156:Gefitinib