Estrogens do not modify MAP kinase-dependent nuclear signaling during stimulation of early G1 progression in human breast cancer cells

S. Caristi, J. L. Galera, F. Matarese, M. Imai, S. Caporali, M. Cancemi, L. Altucci, L. Cicatiello, D. Teti, F. Bresciani, A. Weisz

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Estrogens are direct mitogens for hormone-responsive human breast cancer cells, where they promote cell cycle progression and induce transcriptional activation of "immediate early" and cyclin genes. Nongenomic signaling by estrogens, including rapid changes of mitogen-activated protein (MAP) kinase and other signal-transduction-cascades activity, has been proposed 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 CCNDI 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.

Original languageEnglish
Pages (from-to)6360-6366
Number of pages7
JournalCancer Research
Issue number17
Publication statusPublished - Aug 1 2001

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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