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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s13058-014-0444-4) contains supplementary material, which is available to authorized users.

breast cancer research

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