Requirement for IGF-I in epidermal growth factor-mediated cell cycle progression of mammary epithelial cells

Induction of cyclin proteins is required for progression of cells through the G(1).S and G(2).M cell cycle checkpoints and is a primary mechanism by which mitogens regulate cell cycle progression. IGF-I and the epidermal growth factor (EGF)related ligands are mitogens for mammary epithelial cells in vitro and are essential for growth of the mammary epithelium during development. We report here that IGF-I in combination with EGF or TGFalpha is synergistic in promoting DNA synthesis in mammary epithelial cells in the intact mammary gland cultured in vitro. We further investigated the role of IGF-I and EGF in cyclin expression and cell cycle progression in the mammary gland and demonstrate that IGF-I and EGF induce expression of early G(1) cyclins. However, we show that IGF-I, but not EGF, induces late G, and G(2) cyclins and is required for mammary epithelial cells to overcome the G(1).S checkpoint. These data demonstrate that IGF-I is essential for cell cycle progression in mammary epithelial cells and that it is required for EGF-mediated progression past the G(1).S checkpoint in these cells.