Metastasis, the spreading of the primary tumor to distant organs, is the major cause of failure of breast cancer treatment. Therefore, intervention at a key step of metastatic process, such as angiogenesis, is critical to warrant an effective breast cancer treatment. Vascular endothelial growth factor (VEGF) plays a pivotal role in tumor angiogenesis. Because degree of tumor malignancy directly correlates with the expression of VEGF but inversely correlates with the expression of tumor suppressor gene p16 (p16/Ink 4a), we examined whether restoration of p16 in breast cancer cells that lack endogenous p16 expression would modulate VEGF expression, and if so, how are the effects of p16 expression on tumor angiogenesis and metastasis. To facilitate induction of p16 expression, a recombinant adenovirus expressing p16 (AdRSVp16) was used to transduce breast cancer cell lines MDA-MB-231 and JygMC(A). Our study showed that adenoviral-mediated p16 expression downregulated VEGF expression in breast cancer cells at both mRNA and protein levels, attenuated in vivo angiogenesis induced by breast cancer cells in a dorsal air sac model, and had a 53% reduction of metastases in a spontaneous metastasis animal model compared to the control groups. Moreover, the mechanism for how p16 downregulated VEGF expression was also explored. Taken together, these results demonstrate that adenoviral-mediated p16 expression downregulated VEGF gene expression in breast cancer cells, inhibited breast cancer-induced angiogenesis, and suppressed breast tumor metastasis. This study suggests that blocking tumor angiogenesis may be an effective approach to suppress tumor metastasis, and p16 gene therapy may have clinical potentials to suppress breast cancer growth and metastasis.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA