Ets2 dependent stromal restriction of breast cancer

乳腺癌的 Ets2 依赖性基质限制

• 批准号: 6562872
• 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/6562872
• 关键词: angiogenesis; breast neoplasms; carcinogenesis inhibitor; cell differentiation; gene dosage; gene induction /repression; genetically modified animals; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplastic growth; neoplastic process; protein tyrosine kinase; protooncogene; transcription factor; transfection /expression vector; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：乳腺癌可能是由多种遗传变化引起的，这些变化使腔腔上皮细胞通过日益恶性阶段失去生长控制和进展。尽管在识别与不受管制的生长相关的基因方面取得了进展，但对改变乳腺癌进展的修饰基因的了解却少得多。在小鼠中，将ETS2转录因子的剂量降低了一半，这限制了由癌基因强迫表达引起的乳腺肿瘤的发展。初步结果表明，肿瘤发育的依赖性依赖性限制至少部分是由于乳腺基质作用。这种限制的机制可能涉及募集新血管以允许增生性上皮作为实体瘤生长。 VEGF的强迫表达加速了乳腺肿瘤的外观和限制ETS2延迟肿瘤外观。 ETS2在介导VEGF信号传导中的可能功能将通过产生表达活化的NEU/ERBB2基因，转基因VEGF和一两个突变体ETS2的一两个拷贝的转基因小鼠通过遗传测试。 ETS2在肿瘤轴承小鼠的内皮细胞中的重要性将通过使用RCAS禽流病毒载体和新型的转基因小鼠系，该系列被重组病毒有效感染。最后，通过相互骨髓移植研究研究造血衍生细胞对肿瘤血管生成的重要性。