期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 174, 期 5, 页码 1910-1920出版社
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.080706
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资金
- National Institutes of Health [R01CA70896, R01CA75503, R01CA86072]
- Cancer Center Core grant [P30CA56036]
- Breast Cancer Research Foundation
- Dr. Ralph and Marian C. Falk Medical Research Trust
- Pennsylvania Department of Health
- Grants-in-Aid for Scientific Research [21590081] Funding Source: KAKEN
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)
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