MITOGENIC SIGNAL-TRANSDUCTION IN HUMAN BREAST-CANCER CELLS

1. Signal transduction pathways activated during growth of human breas t cancer cells in tissue culture are reviewed. 2. Steroid hormones and growth factors stimulate similar mitogenic pathways and frequently mo dulate each other's activity. 3. A response common to estrogen, proges tins and most polypeptide mitogens is induction of the nuclear transcr iption factors myc, fos and jun in early G1 phase of the cell cycle. 4 . Some growth factors also stimulate cyclin D1, a regulatory protein r esponsible for the activation of cell cycle-dependent kinases in G1. 5 . In addition, insulin, IGF-I and EGF activate tyrosine kinase recepto rs. 6. Several tyrosine phosphorylated proteins occur in human breast cancer cells, and include the EGF and estrogen receptors. 7. Cyclic AM P plays a critical role in breast cancer cell proliferation through th e activation of protein kinase A, and it also modulates the activity o f estrogen and progesterone receptors. 8. EGF is the only breast cell mitogen known to raise intracellular free calcium levels. 9. Calcium m ay play a dual role in breast cancer cell proliferation, activating bo th calmodulin-dependent processs and regulating cell membrane potentia l through the activation of potassium channels. 10. Potassium channel activity and cell proliferation are linked in breast cancer cells, the cell membrane potential shifting between a depolarized state in G1/G0 cells and a hyperpolarized state during S phase. 11. Activation of an ATP-sensitive potassium channel is required for breast cancer cells t o undergo the G1/G0-S transition.