Mode of EGF action on cell cycle kinetics in human breast cancer cell line MCF-7: some evidence that EGF acts as a "progression factor".

EGF is known to play a very important role in the growth regulation of tumor cells. We have determined the effect of EGF in the absence and in the presence of serum on the cell cycle of MCF-7 cells synchronized in the G1 phase by serum deprivation. In the presence of 1% serum, EGF was found to increase DNA synthesis to 120% of control (P < 0.02), but did not modify the transition time from G1 into S phases, nor the cell doubling time during the first generation following the cell synchronization. The autoradiography analysis of 3H-thymidine labeled cells indicated that, following 24 h of EGF treatment, a constant additional number of cells (11 +/- 1.5%, P < 0.002) were recruited into the S phase in the presence as well as in the absence of serum. These data indicate that EGF exerts its mitogenic effect on MCF-7 cells by increasing the percent of S phase cells without modulating the cell doubling time. However, in the absence of serum a significant increase of thymidine incorporation in whole cells required 12 h of EGF treatment, whereas a 6 h-incubation with EGF was sufficient to stimulate DNA synthesis when synchronized cells were pretreated with serum for 6 h, suggesting that EGF sensitivity is dependent on the cell advance into the G1 phase at the moment of EGF addition. Topographical analysis of 3H-thymidine-labeled cells aimed at determining the spatial distribution of cells in culture revealed that EGF-stimulated cells were disposed near proliferative cells, indicating the local influence on cell proliferation. Taken together, our results suggest that in the MCF-7 cell line, EGF acts in the G1 phase by increasing the proportion of S cells without affecting the duration of the cell cycle. In our model, EGF seems to act as a "progression factor", in that it stimulates only cells already traversing a certain stage in the G1 phase under the action of serum factors, cell secreted diffusible products and cell-cell contact.