INHIBITION OF PROGESTIN-DEPENDENT ANGIOGENESIS IN BREAST CANCER

抑制乳腺癌中孕激素依赖性血管生成

基本信息

批准号：
7628987
负责人：
Candace E Wicks
金额：
$ 0.88万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7628987
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 Cell Culture Techniques Chemopreventive Agent Clinical Trials Curcumin DNA Binding Development 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 Outcome Outcome Study Plant Roots Postmenopause Procedures Production Progesterone Progestins Property RU-486 Rattus Reporter Risk Side Spices Steroid Receptors Therapeutic Agents Toxic effect Treatment Protocols Tumeric Uterus Vascular Endothelial Growth Factors Woman Xenograft Model adduct angiogenesis base body system cancer cell cancer type chemotherapeutic agent combat design in vivo inhibitor/antagonist malignant breast neoplasm neovascularization new growth pre-clinical research study tumor tumor growth tumor progression

项目摘要

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（由申请人提供）：数百万个具有完整子宫的绝经后妇女被处方合并的激素替代疗法（HRT），由雌激素和孕激素组成，以减轻绝经症状；孕激素抵消了子宫中雌激素的增殖作用，这可能导致子宫内膜癌。不幸的是，与仅接受雌激素的女性相比，研究结合了HRT会增加患乳腺癌的风险。因此，有必要设计策略，以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充当抗血管生成和抗癌化合物。然而，尚未研究姜黄素和2-ME2对孕激素驱动的乳腺癌的影响。这项研究的目的是探索姜黄素和2-ME2作为孕激素依赖性乳腺癌的血管生成抑制剂的有效性。假设姜黄素和2-ME2将通过抑制有效的血管生成蛋白血管内皮生长因子（VEGF）抑制孕激素依赖性乳腺癌。为了证明这一假设，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VEGF从人类乳腺癌细胞中分泌。将进行细胞培养分析以调查这一目标；（2）阐明了2-ME2和姜黄素抑制孕激素依赖性VEGF诱导的机制。研究程序包括免疫印迹，荧光素酶报告基因测定和DNA结合分析。（3）确定在DMBA诱导的乳腺癌模型中，姜黄素和2-ME2作为孕激素加速乳腺癌异种移植模型中体内的治疗和预防剂的有效性。这项研究将研究姜黄素和2-ME2可以抑制孕激素依赖性乳腺肿瘤中新血管的生长的可能性。这些实验的积极结果表明，姜黄素和/或2-ME2可以被认为是在经历了激素替代疗法的绝经后妇女中孕妇中孕激素依赖性肿瘤的化学预防或治疗剂。