Modulation of Cyclin Expression by c-Myc in Malignant and Nonmalignant MammaryEpithelial Cells

摘要

The purpose of this grant was to support predoctoral training on an experimentalmodel relevant to breast cancer etiology. Specifically, we explored the multifactorial nature of the interaction a growth factor (TGFalpha, which is commonly expressed both in benign and malignant proliferative disease of the human breast) and an oncogene c-myc, whose gene is amplified and whose protein is inappropriately expressed in 20-30% of human breast tumors. Using a transgenic mouse model we observed that co-expression of these two genes was remarkably synergistic for onset and progression of cell survival and proliferation. While mye induced both p53 and bax death-promoting genes, TCFalpha promoted cell survival by inducing Bc1XL. In terms of the cell cycle, mye shortened G1 by modulating cyc1lin E, p27, and cdc25A, which activated cdk-2 and inactivated Rb. Thus, the interaction of TGFalpha and myc promoted shortened, aberrant cycles resulting in survival of genetically aberrant cells.