A Genetic Dissection of the Role of the ErbB2 IN eu Receptor Tyrosine Kinase in Development and Tumorigenesis in Transgenic Mice.

Abstract

<p>Amplification and overexpression of Neu (HER2, ErbB2) has been observed in a significant proportion of human breast cancers. Consistent with this, overexpression of various neu alleles in the mammary epithelium of transgenic mice resulted in the formation of mammary adenocarcinomas. However, these mouse models have relied upon a hormonally responsive strong viral promoter to direct transgene expression and therefore may not accurately model the human condition. In this thesis I demonstrate that endogenously regulated expressIon of the activated neuNT allele in the mammary gland resulted in increased lateral branching and ductal escape from the fat pad. Upon amplification and overexpression of neuNT, these mice developed adenocarcinomas which shared several similarities with the human disease. I also created a line of mice that express neuNT under the control of the endogenous promoter in the germline. Surprisingly, this did not result in tumor formation, although these mice expressed neuNT at levels equal to the mammary specific activation. I have also examined the role of Neu in the mammary gland through a mammary specific deletion and observed delayed ductal outgrowth. In addition to examining the function ofNeu in the mammary gland, I have also described mice with a conditional deletion of Neu in the skeletal muscle. These mice have profound defects in proprioception due to a lack of muscle spindles, and have a deficiency in muscle regeneration and differentiation. Taken together, these results illustrate the role of Neu in tumorigenesis and in the normal development of numerous other tissues.</p>