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Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-κB and by expression of IκBα-Super Repressor (IκBαSR), a dominant-negative inhibitor for NF-κB. Moreover, the overexpression of IκBαSR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSCenriched populations, was induced by HRG through the activation of the PI3K/NF-κB pathway. These findings illustrate that HRG/ ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-κB pathway in human breast cancer.EGF | HER | tumor sphere | cancer stem cells | inflammation C ancer stem cells (CSCs), which make up only a small proportion of heterogeneous tumor cells, may possess a greater ability to maintain tumorigenesis than other tumor cell types (1, 2). CSCs can self-renew and simultaneously produce differentiated daughter cells; thus they can strongly proliferate until they reach their final differentiated state. With improvements in the isolation of CSCs, there is now a growing body of evidence that, in some cases of hematologic and solid tumors, a cancer stem cell population can be enriched based on phenotype (3-10). In human breast cancers, breast cancer stem cells (BCSCs) are enriched in the CD44 high /CD24 low cell population, whereas the CD44 low / CD24 high cells represent a more differentiated phenotype with limited stem cell-like potential (3). Because BCSCs withstand anoikis in culture, they expand under anchorage-independent conditions, giving rise to clonal spheroids (mammospheres), which can be serially passaged in vitro (11,12). These processes can in part recapitulate the breast tumorigenesis process (13-16). To develop more effective cancer therapies, it would be reasonable to target molecules that have a critical role in the maintenance of mammospheres. However, the molecular mechanism by which mammospheres are maintained is still largely obscure.NF-κB is a transcription factor complex that is typically a heterodimer of p50, p52, p65 (RelA), RelB, and c-Rel. It is usually inactive and bound to IκB, an inhibitory protein, in the cytoplasm. The primary mechanism of regulation of NF-κB activity is through activation of the IKK complex, including heterodimers of IKKα and IKKβ, as a result of various signaling pathways. The serine-threonine kinase Akt is one of the activators of IKKβ (17), and the activated IKK complex phosphorylates the IκBα protein, resulting in its ubiquitination, p...

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The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.