title: FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling.
abstract: Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-κB (NF-κB) in BLBC cells by increasing p65/RelA protein stability. High NF-κB activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-κB for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-κB. These results suggest that BLBC cells may rely on FOXC1-driven NF-κB signaling. Interventions of this pathway may provide modalities for the treatment of BLBC.
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: P S
authors.initials: PS
authors.lastname: Ray
authors.forename: M-S
authors.initials: MS
authors.lastname: Sim
authors.forename: X Z
authors.initials: XZ
authors.lastname: Zhou
authors.forename: K P
authors.initials: KP
authors.lastname: Lu
authors.forename: A V
authors.initials: AV
authors.lastname: Lee
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: S P
authors.initials: SP
authors.lastname: Bagaria
authors.forename: A E
authors.initials: AE
authors.lastname: Giuliano
authors.forename: X
authors.initials: X
authors.lastname: Cui
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018295:Neoplasms, Basal Cell / Q000235:genetics / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051996:Transcription Factor RelA; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase