NF-kappaB Activity in Macrophages Determines Metastatic Potential of Breast Tumor Cells

摘要

The contribution of NF-kappaB (NF-kB) signaling within macrophages to metastatic potential has not been directly investigated in vivo. We use novel transgenic models to address this question during breast to lung metastasis. Expression of an inhibitor (DN) or an activator (IKK) of NF-kB is induced by crossing either inducible transgenic with a second transgenic expressing the reverse transactivator (rtTA) protein in macrophages and administering doxycycline (dox) in drinking water. We have modulated NF-kB activity in macrophages to test effects on breast cancer metastasis to the lung. Using a tail vein model of metastasis we show that increased NF-kB activity in early stages of metastasis results in significant anti-tumor responses and that inhibition of NF-kB activity may have pro-tumor effects. Using the polyoma transgenic model of mammary tumorigenesis we have shown that inhibition of NF-kB may inhibit primary tumor progression. Our data suggest that NF-kB in macrophages influences metastatic potential of mammary tumor cells but that the timing of modulation of NF-kB activity in macrophages may be critical to potential therapeutic response.