An Ets2 dependent stromal restriction of breast cancer

乳腺癌的 Ets2 依赖性基质限制

• 批准号: 6831601
• 负责人: ROBERT GLEN OSHIMA
• 金额: $ 34.18万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831601
• 关键词: Ets2; dependent; stromal; restriction; breast

EXCEED THE SPACE PROVIDED, Breast cancer is likely caused by multiple genetic changes which make luminal epithelial cells lose their growth control and progress through increasingly malignant stages. While progress has been made in identifying genes associated with unregulated growth, much less is known about modifier genes, which influence the progression of breast cancer. Decreasing the dosage of the Ets2 transcription factor by half in mice limits the development of mammary tumors caused by forced expression of an oncogene. Preliminary results indicate that the Ets2 dependent restriction of tumor development is, at least in part, due to a mammary stromal effect. The mechanism of this restriction may involve the recruitment of new blood vessels to permit hyperplastic epithelium to grow as a solid tumor. Forced expression of VEGF accelerates mammary tumor appearance and limiting Ets2 delays tumor appearance. The possible function of Ets2 in mediating VEGF signaling will be tested genetically by generating transgenic mice expressing an activated Neu/ErbB2 gene, transgenic VEGF and one or two copies of a mutant form of Ets2. The importance of Ets2 in endothelial cells of tumor bearing mice will be investigated by use of a RCAS avian retroviral vector and a new transgenic mouse line engineered to be efficiently infected by the recombinant virus. Finally, the importance of hematopoietic derived cells for tumor angiogenesis will be investigated by reciprocal bone marrow transplantation studies. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间，乳腺癌很可能是由多种基因变化引起的，这些变化使管腔上皮细胞失去生长控制并进入日益恶性的阶段。虽然在识别与生长失控相关的基因方面已经取得了进展，但对于影响乳腺癌进展的修饰基因却知之甚少。将小鼠中 Ets2 转录因子的剂量减少一半，可以限制因癌基因强制表达而引起的乳腺肿瘤的发展。初步结果表明，Ets2 依赖性肿瘤发展的限制至少部分是由于乳腺基质效应。这种限制的机制可能涉及招募新血管以允许增生性上皮生长为实体瘤。 VEGF 的强制表达会加速乳腺肿瘤的出现，而限制 Ets2 则会延迟肿瘤的出现。 Ets2 在介导 VEGF 信号传导中的可能功能将通过产生表达激活的 Neu/ErbB2 基因、转基因 VEGF 和一个或两个 Ets2 突变形式的转基因小鼠来进行基因测试。 Ets2在荷瘤小鼠内皮细胞中的重要性将通过使用RCAS禽类逆转录病毒载体和经改造可被重组病毒有效感染的新转基因小鼠系来研究。最后，将通过相互骨髓移植研究来研究造血来源细胞对肿瘤血管生成的重要性。表演网站==========================================部分结束====== =======================================