Nuclear factor-κB enhances ErbB2-induced mammary tumorigenesis and neoangiogenesis in vivo

The (HER2/Neu) ErbB2 oncogene is commonly overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in transgenic mice. Nuclear factor (NF)-κB 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-κB had not previously been determined in immune-competent animals. Furthermore, the role of the NF-κB components, p50 and p65, in tumor growth was not known. Herein, the expression of a stabilized form of the NF-κB-inhibiting IκBα protein (IκBαSR) in breast tumor cell lines that express oncogenic ErbB2 inhibited DNA synthesis and growth in both two- and three-dimensional cultures. Either NF-κB inhibition or selective silencing of p50 or p65 led to a loss of contact-independent tumor growth in vitro. IκBαSR reversed the features of the oncogene-induced phenotype under three-dimensional growth conditions. The NF-κB 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 IκBαSR in breast cancer tumors inhibited angiogenesis. Thus, mammary epithelial cell NF-κB activity enhances ErbB2-mediated mammary tumorigenesis in vivo by promoting both growth and survival signaling via the promotion of tumor vasculogenesis.