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.
