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Progestin Regulation of VEGF in Breast Cancer Cells

孕激素对乳腺癌细胞中 VEGF 的调节

基本信息

批准号：
6865378
负责人：
SALMAN M HYDER
金额：
$ 27.6万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6865378
关键词：
angiogenesis athymic mouse breast neoplasms cell line genetic transcription hormone regulation /control mechanism laboratory mouse laboratory rat mammary gland neoplasm /cancer blood supply neoplasm /cancer transplantation neoplastic growth posttranslational modifications progesterone receptors progestins vascular endothelial growth factors

项目摘要

VEGF is a central regulator of angiogenesis, and cancer is dependent upon this process since tumors cannot grow past a microscope size without the generation of new blood vessels to provide a sufficient nutrient supply. The VEGF system is thus an attractive therapeutic target for disease such as breast and uterine cancer, which require angiogenesis for growth and metastasis. Little is known about the regulation of VEGF expression in hormone related cancers such as those of the mammary gland and endometrium, and it is unclear how one might prevent VEGF expression or actions in these diseases. We have been involved in studying the hormonal regulation of VEGF expression in these tissues, and recently made the novel discovery that progesterone regulates expression of this key angiogenic factor in some human breast cancer cells, specifically in the well characterized T47-D cell line. The aim of this proposal is to determine the molecular mechanisms involved in the regulation of VEGF by progesterone in human breast cancer cells, in normal rodent mammary cells in vivo, in several in vivo mammary tumor models and in human xenografts grown in nude mice. The hypothesis we will test is that progestins (P) regulate transcription of VEGF directly via classical progesterone (PR) mediated signaling pathways. To test this hypothesis we propose 4 specific aims: (1) To determine the mechanism by which progestins regulate expression of VEGF in human breast cancer cells, (2) To determine which form(s) of the PR regulates VEGF expression, the receptor domains necessary for regulation, and the regulatory elements in the VEGF gene that mediate PR induction, (3) To define VEGF regulation by progestins and anti- progestins in vivo in the normal rodent mammary gland, in rodent mammary tumor models and in human tumor xenografts grown in nude mice and (4) to determine if PO induced VEGF in breast cancer cells participates in the process of angiogenesis and tumor growth. Elucidating the mechanisms that control VEGF production in normal and neoplastic mammary cells is essential to understand the regulation of angiogenesis in breast cancer and to design new therapeutic approaches to this disease that modulate VEGF-induced angiogenesis.

VEGF是血管生成的中心调节因子，癌症依赖于这一过程，因为如果没有新血管的生成提供足够的营养供应，肿瘤就无法生长到显微镜下的大小。因此，VEGF系统是乳腺癌和子宫癌等疾病的一个有吸引力的治疗靶点，这些疾病的生长和转移需要血管生成。对于VEGF在激素相关癌症（如乳腺和子宫内膜癌）中的表达调控知之甚少，也不清楚如何在这些疾病中预防VEGF的表达或作用。我们一直在研究激素对这些组织中VEGF表达的调节，最近有了新的发现，黄体酮调节了一些人乳腺癌细胞中这一关键血管生成因子的表达，特别是在已被充分表征的T47-D细胞系中。本研究的目的是确定黄体酮在人乳腺癌细胞、正常啮齿动物体内乳腺细胞、几种体内乳腺肿瘤模型和裸鼠生长的人类异种移植物中调节VEGF的分子机制。我们将验证的假设是，孕激素(P)通过经典的孕激素（PR）介导的信号通路直接调节VEGF的转录。为了验证这一假设，我们提出了4个具体目标：(1)确定孕激素调控人乳腺癌细胞中VEGF表达的机制；(2)确定哪种形式的PR调控VEGF表达，调控所需的受体结构域，以及VEGF基因中介导PR诱导的调控元件；(3)确定正常啮齿动物乳腺中孕激素和抗孕激素对VEGF的体内调控作用。(4)确定PO诱导的乳腺癌细胞中VEGF是否参与血管生成和肿瘤生长过程。阐明正常和肿瘤乳腺细胞中VEGF生成的控制机制对于理解乳腺癌血管生成的调控以及设计调节VEGF诱导血管生成的新治疗方法至关重要。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Estrogen regulation of thrombospondin-1 in human breast cancer cells.

DOI：
10.1002/ijc.24373
发表时间：
2009-09-01
期刊：
International journal of cancer
影响因子：
6.4
作者：
Hyder SM;Liang Y;Wu J
通讯作者：
Wu J

Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors.

DOI：
10.1007/s10549-010-0851-x
发表时间：
2011-01
期刊：
BREAST CANCER RESEARCH AND TREATMENT
影响因子：
3.8
作者：
Liang, Yayun;Besch-Williford, Cynthia;Benakanakere, Indira;Thorpe, Philip E.;Hyder, Salman M.
通讯作者：
Hyder, Salman M.

Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced vascular endothelial growth factor levels in human breast cancer cells.