Regulation of signal transduction for growth factors in mammary epithelial cells.

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Porliferation of the mammary epithelial cell is regulated by growth factors including insulin, IGF-I and EGF.Signal transduction for these growth factors is investigated in many cells. However, the pathway is not completely clarified. To investigate the regulation of growth in the mammary epithelial cell by these growth factors and also investigate their signal transduction pathways, changes in cyclins A,B_1, D_1, D_2, D_3 and E,and cyclin-dependent kinases were analyzed in the mammary epithelial cell. p34^<odc2> and p33^<odk2> were detected by immunoblotting after immunoprecipitation. These proteins were found more in the cell lysate from early pregnant mice of which mammary cells actively grow than in that from lactating cells.The expression of cyclins A,D_2 and E were analyzed by the reverse transcription-polymerase chain reaction. They have shown clear increase during early pregnancy where the proliferation of mammary epithelium is active, suggesting that the regulation of growth by growth factors are through these cyclins. On the other hand, cyclins B_1, D_1 and D_3 did not change very much through pregnancy and lactation. We have further observed a peculiar fact that messenger RNA encoding p21 and p27, tumor suppressor gene-related inhibitors of cyclin, increased during early pregnancy. It is probable that these inhibitors take part in some stage of cell cycle for normally controlled cell division of the epithelium to avoid tumor transformation.To clarify the stage-specific expression of cyclins in the cell cycle, a cell line established from the mammary epithelium was synchronized by serum deprivation. Changes in the expression of cyclin D_1 was examined by the immunoblotting method. Cyclin D_1 level was higher at G_1/S transition than in the prior and later periods.