Progestin Regulation of VEGF in Breast Cancer Cells

孕激素对乳腺癌细胞中 VEGF 的调节

• 批准号: 6625902
• 负责人: SALMAN M HYDER
• 金额: $ 20.99万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625902
• 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

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，因为肿瘤不能生长超过显微镜大小而不产生新血管以提供足够的营养供应。因此，VEGF系统是一个有吸引力的治疗目标，如乳腺癌和子宫癌，这需要血管生成的生长和转移的疾病。关于激素相关癌症如乳腺癌和子宫内膜癌中VEGF表达的调节知之甚少，并且不清楚如何在这些疾病中预防VEGF表达或作用。我们一直参与研究这些组织中VEGF表达的激素调节，最近发现孕酮调节这种关键血管生成因子在某些人乳腺癌细胞中的表达，特别是在充分表征的T47-D细胞系中。本提案的目的是确定孕酮在人乳腺癌细胞、正常啮齿动物乳腺细胞、几种体内乳腺肿瘤模型和裸鼠移植瘤中调节VEGF的分子机制。我们将检验的假设是孕激素（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，我们提出了四个具体目标：（1）确定孕激素调节人乳腺癌细胞中VEGF表达的机制，（2）确定哪种形式的PR调节VEGF表达，调节所必需的受体结构域，以及介导PR诱导的VEGF基因中的调节元件，（3）确定孕激素和抗孕激素在正常啮齿动物乳腺中体内对VEGF的调节，在啮齿动物乳腺肿瘤模型和在裸鼠中生长的人肿瘤异种移植物中，和（4）以确定PO诱导的乳腺癌细胞中的VEGF是否参与血管生成和肿瘤生长的过程。阐明控制VEGF在正常和肿瘤性乳腺细胞中产生的机制对于理解乳腺癌中血管生成的调节和设计调节VEGF诱导的血管生成的这种疾病的新治疗方法至关重要。