17-BETA-ESTRADIOL OVERCOMES A G1 BLOCK INDUCED BY HMG-COA REDUCTASE INHIBITORS AND FOSTERS CELL-CYCLE PROGRESSION WITHOUT INDUCING ERK-1 AND ERK-2 MAP KINASES ACTIVATION

HMG-CoA reductase inhibitors, such as Lovastatin and Simvastatin, caus e cell cycle arrest by interfering with the mitogenic activity of mito gens present in culture media. Cells are induced to pause in G(1) and can readily resume growth upon removal of the enzymatic block. Estroge ns, acting via their nuclear receptor, are mitogens for different norm al and transformed cell types, where they foster cell cycle progressio n and cell division. In estrogen-responsive MCF-7 human breast cancer cells, but not in non responsive cells, 17 beta-estradiol (E(2)) induc es cells arrested with Lovastatin or Simvastatin to proliferate in the presence of inhibitor, without restoring HMG-CoA reductase activity o r affecting the protein prenylation pattern. Mitogenic stimulation of G(1)-arrested MCF-7 cells with E(2) includes primary transcriptional a ctivation of c-fos, accompanied by transient binding in vivo of the es trogen receptor and/or other factors to the ERE and the estrogen-respo nsive DNA region of this proto-oncogene, as detected by dimethylsulpha te genomic footprinting analysis. Mitogenic stimulation of growth-arre sted MCF-7 cells by E(2) occurs, under these conditions, without evide nt activation of ERK-1 and -2 kinases, and thus independently from the mitogen-responsive signal transduction pathways that converge on thes e enzymes.