Abstract
IntroductionThe 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.MethodsUsing 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).ResultsHigh 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.ConclusionsThis 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 materialThe online version of this article (doi:10.1186/s13058-014-0444-4) contains supplementary material, which is available to authorized users.
Highlights
The recently identified claudin-low subtype of breast cancer is enriched for cells with stem-like and mesenchymal-like characteristics
epithelial-to-mesenchymal transition (EMT) cells are more sensitive to glioma-associated oncogene homolog 1 (GLI1) inhibitor human mammary epithelial cells (HMLE)-shEcad cells are HMLE with E-cadherin knockdown [21], which results in EMT associated with mesenchymal-like and stem-like characteristics [7,22]
Epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib profoundly inhibited the proliferation of the control cell lines, while the EMT cell lines were resistant to this treatment, with neither epidermal growth factor receptor (EGFR) inhibitor approaching 50% growth inhibition at concentrations up to 10 μM (Figure S1A-C in Additional file 1)
Summary
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. Claudin-low breast cancers are characterized by low expression levels of cell-cell adhesion molecules including E-cadherin and several of the tight junction claudin proteins, claudin 3, 4, and 7 This subtype is molecularly similar to cells that have undergone an epithelial-to-mesenchymal transition (EMT) and overlaps with the recently characterized mesenchymal and mesenchymal stem-like subclassifications of triple-negative breast cancer [6,7]. Little is known about molecular therapeutic targets in this highly aggressive subtype of breast cancer
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