Despite considerable progress in early diagnosis and treatment of breast and lung cancer, these diseases remain a most significant cause of morbidity and mortality in this country. Understanding the molecular mechanisms governing cellular proliferation in these tumors may provide important insights into alternate strategies for treatment of breast cancer. The long term goals of these studies to understand the mechanisms governing cellular proliferation and the role of cyclin D1 in these events. Recently, the cyclin D1 protein has been strongly implicated in the pathogenesis of several different tumors including breast and lung cancer. Cyclin D1 has several features of an oncogene (cancer inducing gene). Firstly, cyclin D1 levels are increased in a wide variety of tumors including 70-100% of breast tumor cell lines. Secondly, cyclin D1 collaborates with other known oncogenes to transform cells. Thirdly, cyclin D1 inhibits the action of tumor suppressor genes that stop cancer. Fourthly, overexpression of cyclin D1 has been shown to induce breast tumors in transgenic animals. Hormones known to be risk factors for human breast cancer, estrogen and progesterone stimulate cyclin D1 levels. Many growth factors that stimulate proliferation of lung or breast cancer, also stimulate the production of cyclin D1. Recent studies in cultured fibroblasts have suggested that cyclin D1 is the rate limiting step in the early proliferative step induced by serum. It is of interest to determine whether cyclin D1 is rate limiting in mitogenic stimulation of breast cancer cells by growth factors and steroids including progesterone and estrogen.

The aims of these studies are two fold. Firstly, we aim to identify transcriptional activators of cyclin D1 in breast and lung cancer cells. Secondly, we aim to determine whether inducible overexpression of these transcriptional activators can alter endogenous cyclin D1 gene expression and cell-cycle progression in stable cell lines. Comparison will be made with inducible cyclin D1 sense and anti-sense stable cell lines. We aim to thereby determine whether cyclin D1 is rate limiting in the proliferative response to mitogenic stimuli in breast and lung cancer cell lines. Determining whether cyclin D1 is a critical step in the proliferation of breast and lung cancer cells may provide important insights into the mechanisms of tumor growth.

R29CA070896

1996-05-15

2001-02-28