INHIBITION OF PROGESTIN-DEPENDENT ANGIOGENESIS IN BREAST CANCER

抑制乳腺癌中孕激素依赖性血管生成

• 批准号: 7486599
• 负责人: Candace E Wicks
• 金额: $ 2.93万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486599
• 关键词: 2-methoxyestradiol; Address; Adverse effects; Angiogenesis Inhibitors; Angiogenic Factor; Angiogenic Proteins; Anti-Progestin; Antineoplastic Agents; Binding; Biological Assay; Blood Vessels; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Chemopreventive Agent; Clinical Trials; Cultured Cells; Curcumin; DNA Binding; Development; Disruption; Effectiveness; Endometrial Carcinoma; Estrogen Receptors; Estrogens; Fellowship; Glucocorticoid Receptor; Growth; Hormone replacement therapy; Immunoblotting; In Vitro; Individual; Lead; Literature; Luciferases; Malignant Neoplasms; Mammary Neoplasms; Menopausal Symptom; Nude Mice; Numbers; Outcome; Outcome Study; Plant Roots; Postmenopause; Procedures; Production; Progesterone; Progestins; Property; Purpose; RU-486; Rattus; Reporter; Risk; Side; Spices; Steroid Receptors; Therapeutic Agents; Thinking; Toxic effect; Treatment Protocols; Tumeric; Uterus; Vascular Endothelial Growth Factors; Woman; Xenograft Model; adduct; angiogenesis; base; body system; cancer cell; cancer type; chemotherapeutic agent; design; in vivo; inhibitor/antagonist; malignant breast neoplasm; neovascularization; new growth; pre-clinical; research study; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Millions of postmenopausal women with an intact uterus are prescribed combined hormone replacement therapy (HRT), consisting of both estrogens and progestins, to diminish menopausal symptoms; progestins negate the proliferative effects of estrogens in the uterus, which can lead to endometrial cancer. Unfortunately, studies show that combined HRT increases the risk of breast cancer, compared to women who receive estrogens alone. Thus there is a need to design strategies that will negate the proliferative effects of progestins in breast. There is growing evidence that the Indian spice, curcumin, and the estrogen metabolite 2-methoxyestradiol (2-ME2), function as anti-angiogenic and anti-cancer compounds in numerous types of cancer. However, the effects of curcumin and 2-ME2 on progestin-driven breast cancer have not been studied. The purpose of this study is to explore the effectiveness of curcumin and 2-ME2 as angiogenic inhibitors of progestin-dependent breast cancer. It is hypothesize that curcumin and 2-ME2 will inhibit progestin-dependent breast cancer by inhibition the potent angiogenic protein vascular endothelial growth factor (VEGF). To prove this hypothesis, three specific aims will be addressed: (1) Determine whether curcumin and 2-ME2 will inhibit progestin-induced VEGF secretion from human breast cancer cells. Cell culture analysis will be conducted to investigate this aim; (2) elucidate the mechanism by which 2-ME2 and curcumin inhibit progestin-dependent VEGF induction. Investigatory procedures include immunoblotting, luciferase reporter assays, and DNA-binding analysis; and (3) determine the effectiveness of curcumin and 2-ME2 as treatments and preventative agents in vivo in progestin-accelerated breast cancer xenograft model in nude mice in DMBA-induced mammary cancer model. This study will investigate the possibility that curcumin and 2-ME2 can inhibit the growth of new blood vessels in progestin-dependent breast tumors. Positive outcomes from these experiments would suggest that curcumin and/or 2-ME2 could be considered as chemopreventive or therapeutic agents for progestin- dependent tumors in postmenopausal women undergoing combined hormone replacement therapy.

描述(申请人提供)：数百万子宫完整的绝经后妇女被开出由雌激素和孕激素组成的联合激素替代疗法(HRT)，以减轻更年期症状；孕激素抵消了雌激素在子宫中的增殖作用，从而可能导致子宫内膜癌。不幸的是，研究表明，与单独接受雌激素治疗的女性相比，联合使用HRT会增加患乳腺癌的风险。因此，有必要设计一种策略来抵消孕激素在乳房中的增殖作用。越来越多的证据表明，印度香料姜黄素和雌激素代谢产物2-甲氧基雌二醇(2-ME2)在多种类型的癌症中具有抗血管生成和抗癌的作用。然而，姜黄素和2-ME2对孕激素驱动的乳腺癌的作用还没有研究。本研究的目的是探讨姜黄素和2-ME2作为血管生成抑制剂治疗孕激素依赖性乳腺癌的有效性。假设姜黄素和2-ME2通过抑制强大的血管生成蛋白血管内皮生长因子(VEGF)来抑制孕激素依赖性乳腺癌。为了证明这一假说，将解决三个具体目标：(1)确定姜黄素和2-ME2是否会抑制孕激素诱导的人乳腺癌细胞分泌血管内皮生长因子。将进行细胞培养分析以探讨这一目的；(2)阐明2-ME2和姜黄素抑制孕激素依赖性血管内皮生长因子诱导的机制。研究程序包括免疫印迹、荧光素酶报告分析和DNA结合分析；(3)确定姜黄素和2-ME2在体内对孕激素加速的乳腺癌裸鼠移植瘤模型和DMBA诱导的乳腺癌模型的治疗和预防效果。本研究将探讨姜黄素和2-ME2抑制孕激素依赖性乳腺肿瘤新生血管生长的可能性。这些实验的阳性结果表明，姜黄素和/或2-ME2可以被认为是接受联合激素替代治疗的绝经后妇女孕激素依赖性肿瘤的化学预防或治疗药物。