): The overall goal of this application is to acquire the opportunity to develop the skills and knowledge to become an independent investigator who can compete successfully for future grant support. By integrating molecular biologic skills with her clinical interest in surgical oncology, Dr. Gadd hopes to become facile at translating findings in the laboratory into the clinical arena in order to improve patient care. Developing a solid research foundation is one of the key elements to achieving a successful and productive academic career in surgical oncology. The objectives of this proposal are to identify oncogenes that collaborate with cyclin D1 in the development of breast cancer and to determine how cyclin D1 levels are regulated in normal cells. Cyclin D1 is a tightly regulated cell cycle protein that is required by eukaryotes for DNA synthesis. In as many as 50% of primary human breast cancers cyclin D1 levels are overexpressed. Consistent with this finding in breast cancer is the association between overexpression of cyclin D1 and the development of mammary tumors in transgenic mice. Together these data lend support to the notion that cyclin D1 is an oncogene and cooperates with other oncogenes in the development of breast cancer. Interestingly, cyclin D1 gene amplification accounts for only a small percentage of cyclin D1 overexpression in human breast cancers. Therefore alternative mechanisms must be involved in the deregulation of cyclin D1 expression. A considerable amount of evidence suggests that post-transcriptional mechanisms are involved in maintaining strict control over cyclin D1 expression. Identification of these control mechanisms and the oncogenes that collaborate with cyclin D1 in the development of breast carcinomas will clarify new approaches to restore the regulatory pathways that prevent breast epithelial cell carcinogenesis. The research environment at the Massachusetts General Hospital, Harvard Medical School, and in the surrounding Boston area includes an abundant resource of scientists, technologies and collaborative opportunities. In addition to the basic science courses offered at Harvard Medical School there are numerous lectures and seminars on a wide variety of related topics. Included within the core of scientists at the Massachusetts General Hospital are experts in the fields of cell cycle regulation, transcriptional and post-transcriptional control, signal transduction, yeast and Drosophila genetics, and chromosomal analysis.
