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ABSTRACT (Maximum 200 Words)This project aims to elucidate the cell cycle basis on which c-myc oncogene induces mammary carcinogenesis and transforming growth factor o (tgfcx) promotes the process. Conduction of this training project will help the P.1. to develop his career in breast cancer research. Data obtained so far have shown that c-myc transgenic mammary tumors may develop specific foci that are more aggressive than their adjacent tumor areas and thus represent a second stage of tumor progression. c-Myc may induce E2F1 and cyclin A2 to initiate the tumor development, whereas overexpression of cyclins DI and E may occur as later events to promote tumor progression to a more aggressive phenotype. TGFcc may enhance c-Myc-induced mammary carcinogenesis by inducing cyclin DI and facilitating the loss of pRB expression, resulting in an earlier development of more aggressive tumors in tgfa/c-myc double transgeneic mice, compared to the c-myc tumors. These findings in the transgenic animals may have relevance to human breast cancer.
INTRODUCTION:This subject of study aims to elucidate the cell cycle basis on which c-myc oncogene initiates mammary carcinogenesis and transforming growth factor (X (tgfa) promotes the process. Conduction of this training project will help the P.I., Dr. Dezhong Liao, to develop his career in breast cancer research. This research project has four tasks, each of which is consisted of two parts, i.e. in vivo studies with transgenic mice and in vitro studies with cultured cells. The four tasks are: "* Task 1. Study whether expression of E2F1 and cyclin A2 is induced to mediate mammary cancer formation in c-myc mice. (Months 1-15). "* Task 2. Investigate whether c-myc initially suppresses cyclin DI expression, but overexpression of cyclins DI and E occurs as later events to facilitate progression of tumors to faster growing phenotypes. (Months 1-15) "* Task 3. Study the mechanisms and the roles of overexpression of cyclins DI and E in mammary carcinogenesis in TGFc/c-myc mice. . "* Task 4. Investigate the mechanisms for the loss of pRB during mammary carcinogenesis in myc and TGFcu/c-myc mice. BODY:1. In vivo animal experiments on the cell cycle basis of c-myc-induced, tgfu.-enhanced mouse mammary carcinogenesis: We have actually started the project since this proposal was submitted to DOD in June of 1999, about one year earlier than the time when the award was started. During the past two years, ...
