Polyamines and Breast Cancer Biology

多胺与乳腺癌生物学

• 批准号: 6889591
• 负责人: ANDREA MANNI
• 金额: $ 31.76万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889591
• 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）：

项目成果

Biological activity of the S-adenosylmethionine decarboxylase inhibitor SAM486A in human breast cancer cells in vitro and in vivo.

S-腺苷甲硫氨酸脱羧酶抑制剂 SAM486A 在体外和体内人乳腺癌细胞中的生物活性。

• 发表时间: 2004
• 期刊: International journal of oncology.
• 作者: Hu,Xin;Washington,Sharlene;Verderame,MichaelF;Demers,LaurenceM;Mauger,David;Manni,Andrea
• 通讯作者: Manni,Andrea

Activation of protein kinase A (PKA) signaling mitigates the antiproliferative and antiinvasive effects of alpha-difluoromethylornithine in breast cancer cells.

蛋白激酶 A (PKA) 信号传导的激活可减轻 α-二氟甲基鸟氨酸在乳腺癌细胞中的抗增殖和抗侵袭作用。

• DOI: 10.1007/s10549-007-9536-5
• 发表时间: 2008
• 期刊: Breast cancer research and treatment
• 影响因子: 3.8
• 作者: Xu,Haifang;Washington,Sharlene;Verderame,MichaelF;Manni,Andrea
• 通讯作者: Manni,Andrea