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.
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Supported in part by the National Institutes of Health (grants R01CA70896, R01CA75503, and R01CA86072 to R.G.P., and Cancer Center Core grant P30CA56036 to the Kimmel Cancer Center to R.G.P.), the Breast Cancer Research Foundation (to A.A.Q.), the Dr. Ralph and Marian C. Falk Medical Research Trust (to R.G.P.), and the Pennsylvania Department of Health (to R.G.P.). The Pennyslvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.
A guest editor acted as editor-in-chief for this manuscript. No person at Thomas Jefferson University was involved in the peer review process or final disposition for this article.
