Mechanism of Regression of c-MYC-Induced Mammary Tumors in a Conditional Transgenic Model

摘要

The pathways stimulated by the oncogenes HER2/Neu/ErbB2, Wnt-l, and H-ras are aberrantly activated in many human cancers, including breast cancer, and have been shown to play a role in carcinogenesis. In order to better investigate the role these genes play in breast cancer, we generated mouse models that inducibly express activated forms of these oncogenes in the mammary gland. This system allows us to activate these oncogenic pathways during specific windows of mammary gland development, as well as to remove the initiating oncogenic stimulus after the development of a tumor or during later stages of tumor progression. As such, we anticipate that the study of these models will provide valuable insights into the mechanisms by which activation of these pathways contributes to breast cancer development or progression, and will ultimately aid in the generation of therapeutic strategies that specifically target these pathways. We have found that expression of Neu in the mammary glands of transgenic mice results in the development of both invasive adenocarcinomas and pulmonary metastases that remain dependent upon Neu expression for maintenance of the transformed state. We have also determined that both Wnt-l and c-Myc synergize with Neu in mammary tumorigenesis.