An Ets2 dependent stromal restriction of breast cancer

乳腺癌的 Ets2 依赖性基质限制

基本信息

批准号：
7154754
负责人：
ROBERT GLEN OSHIMA
金额：
$ 32.41万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
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/7154754
关键词：
Acceleration Alleles Angiogenic Switch Animals Appearance Binding Birds Blood Vessels Bone Marrow Bone Marrow Transplantation Breeding Carcinoma Cell Nucleus Cells Development Endothelial Cells Engineering Epithelial Cells Epithelium Female Gene Expression Genes Genotype Growth Hematopoietic Hematopoietic System Hyperplasia Inflammatory Lactation Malignant - descriptor Mammary Neoplasms Mammary gland Marrow Matrix Metalloproteinases Mediating Mediator of activation protein Mouse Mammary Tumor Virus Mus Mutation Numbers Oncogenes Oncogenic Retroviral Vector Retroviridae Role Signal Transduction Solid Neoplasm Staging Testing Threonine Transgenes Transgenic Mice Transgenic Organisms Transplantation Tumor Angiogenesis Vascular Endothelial Growth Factors desire dosage malignant breast neoplasm mutant receptor recombinant virus recombinase reconstitution transcription factor tumor tumor growth

项目摘要

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.

乳腺癌可能是由多种遗传变化引起的，这些变化使腔内皮细胞失去了通过越来越恶性的阶段，成长控制和进步。虽然进展已取得识别与不受管制的生长相关的基因，更不用说关于修饰基因的知之甚少，这些基因已知影响乳腺癌的进展。将ETS2转录因子的剂量降低一半小鼠限制了由癌基因强迫表达引起的乳腺肿瘤的发展。初步的结果表明，肿瘤发育的ETS2依赖性限制至少部分是由于乳腺基质效应。该限制的机制可能涉及招募新血管以允许增生性上皮作为实体瘤生长。 VEGF强迫表达加速乳腺肿瘤外观和限制ETS2延迟肿瘤外观。 ETS2在介导VEGF中的可能功能信号传导将通过产生表达活化的neu/erbb2基因的转基因小鼠通过遗传测试。转基因VEGF和一两个副本的ETS2突变形式。 ETS2在内皮细胞中的重要性肿瘤轴承小鼠的使用将通过使用RCAS禽流病毒载体和新的转基因来研究小鼠线设计为有效地被重组病毒感染。最后，重要性造血衍生的细胞用于肿瘤血管生成，将通过相互骨髓研究移植研究。