title: Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway.
abstract: BACKGROUND
  The recently identified claudin-low subtype of breast cancer is enriched for cells with stem-like and mesenchymal-like characteristics. This subtype is most often triple-negative (lacking the estrogen and progesterone receptors (ER, PR) as well as lacking epidermal growth factor 2 (HER2) amplification) and has a poor prognosis. There are few targeted treatment options available for patients with this highly aggressive type of cancer.
  
  
  METHODS
  Using a high throughput inhibitor screen, we identified high expression of glioma-associated oncogene homolog 1 (GLI1), the effector molecule of the hedgehog (Hh) pathway, as a critical determinant of cell lines that have undergone an epithelial to mesenchymal transition (EMT).
  
  
  RESULTS
  High GLI1 expression is a property of claudin-low cells and tumors and correlates with markers of EMT and breast cancer stem cells. Knockdown of GLI1 expression in claudin-low cell lines resulted in reduced cell viability, motility, clonogenicity, self-renewal, and reduced tumor growth of orthotopic xenografts. We observed non-canonical activation of GLI1 in claudin-low and EMT cell lines, and identified crosstalk with the NFκB pathway.
  
  
  CONCLUSIONS
  This work highlights the importance of GLI1 in the maintenance of characteristics of metastatic breast cancer stem cells. Remarkably, treatment with an inhibitor of the NFκB pathway reproducibly reduces GLI1 expression and protein levels. We further provide direct evidence for the binding of the NFκB subunit p65 to the GLI1 promoter in both EMT and claudin-low cell lines. Our results uncover crosstalk between NFκB and GLI1 signals and suggest that targeting these pathways may be effective against the claudin-low breast cancer subtype.
authors.forename: Sierra A
authors.initials: SA
authors.lastname: Colavito
authors.forename: Mike R
authors.initials: MR
authors.lastname: Zou
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.forename: Don X
authors.initials: DX
authors.lastname: Nguyen
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D057167:Claudins / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; D057167:Claudins; C400551:GLI1 protein, human; D006574:Heterocyclic Compounds, 2-Ring; C525593:JK184; D016328:NF-kappa B; D012333:RNA, Messenger; D013844:Thiazoles; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1