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Estrogens Do Not Modify MAP Kinase-dependent Nuclear Signaling during Stimulation of Early G₁ Progression in Human Breast Cancer Cells¹

Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli, 80138 Napoli [S. Car., J. L. G., F. M., M. I., S. Cap., M. C., L. A., L. C., F. B., A. W.], and Dipartimento di Patologia e Microbiologia sperimentale, Università degli Studi di Messina, 98125 Messina [D. T.], Italy

Estrogens are direct mitogens for hormone-responsive human breast cancercells, where they promote cell cycle progression and induce transcriptionalactivation of "immediate early" and cyclin genes. Nongenomic signalingby estrogens, including rapid changes of mitogen-activated protein(MAP) kinase and other signal-transduction-cascades activity, has beenproposed to be essential for the mitogenic actions of these hormones and their nuclear receptors. Because regulation of gene transcription is considered a key step in cell cycle control by mitogenic protein kinase cascades, here we investigated the possibility that estrogen might induce the activation of extracellular signal-regulated kinase (Erk) 1/2-, c-Jun NH₂-terminal kinase-, p38- or protein kinase A-responsive transcription factors in the cell nucleus during stimulation of early G₁ progression, a timing coincident with the maximum effects of these hormones on such enzyme activity. No significant changes in protein kinase-mediated transcription factor activity could be detected here after estrogen stimulation of either MCF-7 or ZR-75.1 cells. Furthermore, these steroids were able to induce activation of the human CCND1 gene promoter, accumulation of cyclin D1 and pRb phosphorylation, all key events in cell cycle stimulation by mitogens, even in the presence of Erk1/2 activation blockade by a MAP kinase-activating kinase (Mek)1/2 inhibitor. Thus, estrogens do not appear to convey significant protein kinase-dependent signaling to the cell nucleus during the early phases of human breast cancer cell stimulation. Furthermore, hormonal regulation of G₁ gene transcription can occur even without additional activation of the Mek-Erk1/2 pathway by estrogen receptors.

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