The over-reaching goal of this proposal is to provide a biological basis for the incorporation of inhibitors of the polyamine (PA) pathway in the adjuvant therapy of human breast cancer. The rationale for the proposed studies derives from our preliminary finding that inhibition of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in PA biosynthesis, suppresses pulmonary metastasis from human breast cancer orthotopic xenografts in nude mice.
Specific Aim 1 will address the role of ODC in metastasis, focusing both on its """"""""permissive"""""""" effect when expressed at physiological levels as well as its """"""""potentiating"""""""" action when overexpressed, as frequently observed in clinical breast cancer.
Specific Aim 2 will investigate the influence on metastasis of Sadenosylmethionine decarboxylase (SAMDC), the other highly regulated PA biosynthetic enzyme involved in the synthesis of the more distal PA, spermidine and spermine. We plan to test the hypothesis that SAMDC overexpression in the presence of increased ODC activity will augment the metastatic phenotype by inducing global activation of the pathway. These experiments will provide the necessary preclinical data for optimal implementation of SAMDC inhibitors (alreadyin Phase I trials) in the adjuvant therapy of breast cancer.
Specific Aim 3 will investigate the cellular mechanisms by which different components of the PA pathway (e.g., ODC, SAMDC, and ODC + SAMDC) influence the metastatic properties of human breast cancer cells. Specifically, we will focus on PA effects on integrin-induced activation of proteases and on the cross talk between integrin and growth factor signaling. The ultimate goal of these studies is to identify critical signaling molecules which can be targeted in conjunction with antipolyamine therapy to optimize prevention of metastasis from breast cancer.
