Nuclear Factor-κB Enhances ErbB2-Induced Mammary Tumorigenesis and Neoangiogenesis in Vivo

The (HER2/Neu) ErbB2 oncogene is commonly over-expressed in human breast cancer and is sufficient for mammary tumorigenesis in transgenic mice. Nuclear factor (NF)-kappa B activity is increased in both human and murine breast tumors. The immune response to mammary tumorigenesis may regulate tumor progression. The role of endogenous mammary epithelial cell NF-kappa B had not previously been determined in immune-competent animals. Furthermore, the role of the NF-kappa B components, p50 and p65, in tumor growth was not known. Herein, the expression of a stabilized form of the NF-kappa B-inhibiting I kappa B alpha protein (I kappa B alpha SR) in breast tumor cell lines that express oncogenic ErbB2 inhibited DNA synthesis and growth in both two- and three-dimensional cultures. Either NF-kappa B inhibition or selective silencing of p50 or p65 led to a loss of contact-independent tumor growth in vitro. I kappa B alpha SR reversed the features of the oncogene-induced phenotype under three-dimensional growth conditions. The NF-kappa B blockade inhibited ErbB2-induced mammary tumor growth in both immune-competent and immune-deficient mice. These findings were associated with both reduced tumor microvascular density and a reduction in the amount of vascular endothelial growth factor. The expression of I kappa B alpha SR in breast cancer tumors inhibited angiogenesis. Thus, mammary epithelial cell NF-kappa B activity enhances ErbB2-mediated mammary tumorigenesis in vivo by promoting both growth and survival signaling via the promotion of tumor vasculogenesis. (Am J Pathol 2009, 174:1910-1920; DOI: 10.2353/ajpath.2009.080706)