Over twenty distinct transforming genes have been identified in the genomes of oncogenic retroviruses. Each of these oncogenes has a homologue in the chromosomal DNA of a vertebrate species. Current evidence indicates that this highly conserved set of genes may play a vital role in cell proliferation and/or differentiation. In addition, inappropriate expression of some of these genes has been implicated in the genesis of cancer. Our hypothesis is that deregulation of oncogene expression may be a possible general mechanism for the induction of neoplasia in humans. Our efforts have been concentrated on the cellular homologue in the ras gene, the oncogene carried by Harvey and Kirsten Sarcoma viruses. In this study we are investigating the role of ras gene expression in the induction of rat and human mammary carcinomas. In a study of more than 200 human breast carcinomas. We have observed elevated expression of c-rasH in 70% of estrogen and progesterone receptor positive tumors and 40% of estrogen and progesterone receptor negative tumors. Whereas, an amplified or rearranged c-rasH gene has not been detected in human mammary carcinomas. Thus, the mechanism by which c-rasH gene expression is deregulated in these mammary tumors remain to be determined. To study the mechanism of the enhanced c-rasH gene expression, we will determine the c-rasH expression in growing and growth-arrested human breast cancer cells (MCF-7), growing vs regressing rat mammary tumors, hormone-dependent vs hormone-independent tumors, and the mammary gland of rodents during normal development and chemical or viral carcinogenesis. Moreover, using a new acceptor cell line, the mouse mammary epithelial cell line (NmuMG) for transfection experiments, we will investigate the intracellular factors those regulate the expression of c-rasH gene. The goal of this proposal is to provide us a fundamental basis for better understanding the mechanisms by which oncogenes involved in the neoplastic development and growth.
