Invasion and metastasis of cancer cells is a complex process requiring the activity of proteins that promote extracellular matrix degradation, motility of cancer cells and angiogenesis. The proteins required for this process are derived not only from the cancer cells but also from stromal fibroblasts in response to cancer cell-stromal cell interactions. The expression of a number of genes that promote metastasis is controlled by the transcription factor NF-kappaB. NF-kappaB is usually maintained in an inactive state in the cytoplasm by protein-protein interaction with inhibitor IkappaBs by extracellular signals. Recently, we and others have demonstrated that about60 percent of breast cancer cell lines and primary breast cancers contain constitutively active NF-kappaB secrete IL-1alpha which induces NF-kappaB in fibroblasts. IL-1alpha induced the expression of uPA, IL-6, IL-8 and matrix metalloproteinase-3 (MMP-3) in fibroblasts. Neutralizing antibody against IL-1alpha reduced IL-6 and IL-8 in breast cancer cells in a cell type-dependent manner. Recent studies indicate that MMP-3, which is expressed only in stromal fibroblasts, is essential for initiation of mesenchymal-like mammary tumors. uPA along with urokinase plasmitogen activator receptor (uPAR) and MMP-9 are essential for intravasation of cancer cells. Increased IL-6, uPA and MMP-3 correlates with advanced stage of the disease and/or poor prognosis in breast cancer. Based on these observations, we hypothesize that breast cancer cell derived IL-1alpha plays an important role in increasing IL-6, uPA and MMP-3 expression, thereby contributing to progression of disease to advanced stage. Moreover, IL-1alpha may promote colonization, angiogenesis and subsequent growth of cancer cells at the target site due to induction of MMPs and IL-8. Our key goal is to determine whether inhibition of IL-1alpha activity retards the growth and metastasis of experimental breast cancers. This will be addressed by: 1) evaluating the growth and metastasis of IL-1alpha expressing MDA-MB-231 cells in nude mice with or without anti-IL-1alpha antibody treatment; 2) study the growth and metastasis of MCF-7 cells overexpressing IL-1alpha in nude mice; 3) study the in vitro growth and matrigel invasion of MDA-MB-231 cells in which pre- IL-1alpha processing is inhibited by either cell permeable inhibitors or calpastatin overexpression. This exploratory research is essential for the development of therapeutic agents targeted against IL-1alpha.
| Helbig, Gregory; Christopherson 2nd, Kent W; Bhat-Nakshatri, Poornima et al. (2003) NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278:21631-8 |
| Kumar, Suresh; Kishimoto, Hiromitsu; Chua, Hui Lin et al. (2003) Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer. Am J Pathol 163:2531-41 |
| Nakshatri, Harikrishna; Goulet Jr, Robert J (2002) NF-kappaB and breast cancer. Curr Probl Cancer 26:282-309 |
