Abstract 4218: Potential roles of NF-kappa B pathways in breast cancer-initiating cells

Abstract

Abstract Accumulating evidence suggests that Tumor-initiating cells (TICs) or cancer stem cells_which make up only a small proportion of heterogeneous tumor cells_possess a greater ability to maintain tumor formation than other tumor cell types. In human breast cancers, a population characterized by the expression of cell surface markers, CD24−/low/CD44+, was reported to be highly enriched in TICs as compared to CD24+/CD44+ cell populations. However, the signaling pathways activated in TICs that contribute to tumorigenesis are not fully understood. We observed various expression levels of CD24 and CD44 among 8 human breast cancer cell lines. The CD24−/low/CD44+ cell populations of HCC1954 and MCF7, breast cancer cell lines, generated significantly larger tumors than the CD24+/CD44+ cell populations in a xenograft model, suggesting that the CD24−/low/CD44+ cell populations have the properties of TICs at some extent. To identify expressed genes that were highly enriched in CD24−/low/CD44+ cell populations, we next performed DNA microarray analysis using HCC1954, MCF7, and HCC70 cell lines that have small populations of CD24−/low/CD44+ cells. We then applied a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. GSEA revealed that the CD24−/low/CD44+ cell populations are enriched for genes involved in a tumor necrosis factor (TNF) or interferon (IFN) response pathway. TNF or IFN response pathway is involved in the expression of many inflammatory cytokines/chemokines, including IL8 and CCL5. We measured expression levels of IL8 and CCL5 by quantitative RT-PCR (qRT-PCR) and confirmed that they were expressed at significantly higher levels in CD24−/low/CD44+ cell populations compared with the CD24+/CD44+ cell populations. Moreover, we found the relatively high nuclear factor kappa B (NF-kappa B) activity in the CD24−/low/CD44+ cell populations. In addition, NF-kappa B inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) prevented tumorigenesis of CD24−/low/CD44+ cell populations in vivo. Our findings suggest that NF-kappa B play a crucial role for orchestration of transcription factors regulating breast cancer stem cell biology. Further studies will be presented about the mechanism of NF-kappa B activation and its role in breast TICs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4218.