Many human tumors, including breast cancer, display a hierarchical organization in which a subset of tumor cells with stem cell properties drives tumor growth and metastasis. Recent studies have shown that cancer stem cells (CSCs) are regulated by intrinsic self-renewal pathways in addition to extrinsic inflammatory pathways. Overexpression of HER2 has been shown to increase the CSC population but the underlying molecular mechanism is still largely unknown. We have systematically dissected the HER2-downstream signaling pathways and found that the NFkB and STAT3 pathways are the most important for self-renewal of CSCs. Interestingly, activation of NFkB and STAT3 is not directly mediated by signaling molecules immediately downstream of HER2, such as MAPK or PI3K/AKT kinases, but instead is mediated by HER2-induced interleukin-1 (IL-1) and interleukin-6 (IL-6) cytokines. IL-1 is a well-known proinflammatory cytokine that can induce the expression of a cascade of cytokines including IL-6 to propagate and sustain inflammation. Therefore, we hypothesize that HER2 induction of IL-1 serves as an important link between inflammation and cancer stem cells that switches on a cascade of cytokines in both tumor and stromal cells to regulate the CSC population in vivo. To test this hypothesis, we will pursue the following specific aims.
In Aim 1, we will elucidate the molecular mechanism by which HER-2 regulates the expression of IL-1 and IL-6 in breast cancer cells. Using a series of biochemical approaches, we will first identify the key HER2-downstream signaling pathways responsible for induction of IL-1 expression in breast cancer cells and address whether IL1 in turn activates IL- 6 expression.
In aim 2, we will study the function and mechanism of HER2-induced IL-1 and IL-6 signaling in the maintenance and regulation of cancer stem cells. We will use recombinant proteins and knockdown cell models to study how the interplay between IL-1-induced NFkB signaling and IL-6-induced STAT3 signaling regulates the CSC population.
In aim 3, we will investigate the sources and functions of IL-1 and IL-6 in promotion of HER2-induced mammary tumorigenesis. We will cross MMTV-Her2 transgenic mice with IL-1 and IL-6 knockout mice models to study the functions of these two cytokines in Her2/neu-induced tumor onset and progression. Successful completion of this study will help us understand the mechanism and functions of HER2-induced IL1 and IL6 cytokines in the generation and maintenance of the CSC population both in vitro and in vivo.
Genomic amplification or overexpression of HER2 occurs in 20-30% of breast cancers and correlates with poor prognosis. HER2-targeted drugs, such as HER2 antibody and kinase inhibitors, are effective in treating HER2-postitive breast cancer. However, most patients ultimately develop resistance to such drugs, necessitating the identification of new therapeutic strategies, such as targeting cancer stem cells. Our results indicate that the IL-1 and IL-6 cytokines play a critical role in HER2-induced expansion of cancer stem cells and tumorigenesis. Thus, the targeting of IL-1 or IL-6 offers an opportunity for the treatment of HER2-positive breast cancer.
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