Abstract
The capacity of breast cancer cells to form mammospheres in non-adherent serum-free culture is used as a functional characteristic of the self-renewing stem-like cell population. The present studies demonstrate that silencing expression of the MUC1-C oncoprotein inhibits growth of luminal MCF-7 and HER2-overexpressing SKBR3 breast cancer cells as mammospheres. We also show that triple-negative MDA-MB-468 breast cancer cells are dependent on MUC1-C for growth as mammospheres and tumor xenografts. Similar results were obtained when MUC1-C function was inhibited by expression of a MUC1-C(CQCAQA) mutant. Moreover, treatment with the MUC1-C inhibitor GO-203, a cell penetrating peptide that binds to the MUC1-C cytoplasmic domain and blocks MUC1-C function, confirmed the importance of this target for self-renewal. The mechanistic basis for these findings is supported by the demonstration that MUC1-C activates NF-κB, occupies the IL-8 promoter with NF-κB, and induces IL-8 transcription. MUC1-C also induces NF-κB-dependent expression of the IL-8 receptor, CXCR1. In concert with these results, targeting MUC1-C with GO-203 suppresses IL-8/CXCR1 expression and disrupts the formation of established mammospheres. Our findings indicate that MUC1-C contributes to the self-renewal of breast cancer cells by activating the NF-κBIL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population.
Highlights
Normal tissues contain stem cell populations that renew through asymmetrical division and give rise to progenitors committed to functional differentiation [1]
Mucin 1 (MUC1)-C silencing resulted in a significant reduction in mammosphere formation as indicated by marked decreases in both sphere size (Fig. 1F, left) and sphere www.impactjournals.com/oncotarget forming efficiency (SFE) (Fig. 1F, right), indicating that MUC1-C is of functional importance for growth of breast cancer cells under anchorage-independent conditions
Little is known about whether MUC1-C is of importance for the growth and survival of breast cancer cells that have the capacity for self-renewal
Summary
Normal tissues contain stem cell populations that renew through asymmetrical division and give rise to progenitors committed to functional differentiation [1]. Debate remains about the definition of cancer stem-like cells as a result of their heterogeneity and plasticity [4, 5]. Aldehyde dehydrogenase (ALDH) activity has been a focus of study as a marker for both normal and cancer stem cells [6]. Many of these markers are not exclusively expressed by cancer stem-like cells and the available evidence indicates that there is considerable phenotypic heterogeneity within these populations [4, 5]. Interleukin-8 (IL-8), an inflammatory cytokine that is upregulated in breast cancer and is associated with a poor prognosis [14], has been identified as an important regulator of EMT, stem-like cell activity and mammosphere formation [1518]
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