Polyamines and Breast Cancer Biology

多胺与乳腺癌生物学

• 批准号: 6764091
• 负责人: ANDREA MANNI
• 金额: $ 30.84万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-20 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764091
• 关键词: antineoplastics; athymic mouse; biological products; biosynthesis; breast neoplasms; combination chemotherapy; decarboxylases; difluoromethylornithine; endopeptidases; enzyme activity; enzyme inhibitors; growth factor; integrins; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; neoplasm /cancer pharmacology; oncology; ornithine decarboxylase; polyamines; spermidine; spermine; technology /technique development

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.

描述（由申请人提供）： 本研究的目标是为多胺（PA）通路抑制剂在乳腺癌辅助治疗中的应用提供生物学基础。所提出的研究的基本原理来自于我们的初步发现，即抑制鸟氨酸脱羧酶（ODC），PA生物合成中的第一个和限速酶，抑制人乳腺癌裸鼠原位异种移植瘤的肺转移。具体目标1将解决ODC在转移中的作用，重点是其在生理水平表达时的“允许”作用以及在过表达时的“增强”作用，如在临床乳腺癌中经常观察到的。具体目标2将研究对腺苷甲硫氨酸脱羧酶（SAMDC）转移的影响，SAMDC是参与更远端PA、亚精胺和精胺合成的另一种高度调节的PA生物合成酶。我们计划检验这一假设，即在ODC活性增加的情况下，SAMDC过表达将通过诱导途径的全面激活来增加转移表型。这些实验将为SAMDC抑制剂（已在I期试验中）在乳腺癌辅助治疗中的最佳实施提供必要的临床前数据。具体 目的3将研究PA通路的不同组分（例如，ODC、SAMDC和ODC + SAMDC）影响人乳腺癌细胞的转移特性。具体来说，我们将集中在PA的影响整合素诱导的激活蛋白酶和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结合使用，以优化乳腺癌转移的预防。