Polyamines and Breast Cancer Biology

描述(由申请人提供)： 这一建议的超常目标是为将多胺(PA)途径的抑制剂纳入人类乳腺癌的辅助治疗提供生物学基础。这项研究的基本原理来自于我们的初步发现，抑制鸟氨酸脱羧酶(ODC)是PA生物合成中的第一个也是限速酶，可以抑制人乳腺癌裸鼠原位移植瘤的肺转移。具体目标1将讨论ODC在转移中的作用，重点放在它在生理水平表达时的“允许”作用以及在过度表达时的“增强”作用，就像临床乳腺癌中经常观察到的那样。特定目的2将研究腺苷蛋氨酸脱羧酶(SAMDC)对转移的影响，SAMDC是另一种高度调控的PA生物合成酶，参与合成更远端的PA、亚精胺和精胺。我们计划测试这样一种假设，即在ODC活性增加的情况下SAMDC的过度表达将通过诱导该通路的整体激活来增强转移表型。这些实验将为SAMDC抑制剂在乳腺癌辅助治疗中的最佳实施提供必要的临床前数据(已经在I期试验中)。特定的 目的3研究PA通路的不同成分(如ODC、SAMDC和ODC+SAMDC)影响人乳腺癌细胞转移特性的细胞机制。具体地说，我们将集中在PA在整合素诱导的蛋白酶激活中的作用，以及整合素和生长因子信号之间的串扰。这些研究的最终目标是确定关键的信号分子，这些分子可以与抗多胺治疗一起靶向，以优化乳腺癌转移的预防。

DESCRIPTION (provided by applicant): 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.