S. Caristi et al., Estrogens do not modify MAP kinase-dependent nuclear signaling during stimulation of early G(1) progression in human breast cancer cells, CANCER RES, 61(17), 2001, pp. 6360-6366
Estrogens are direct mitogens for hormone-responsive human breast cancer ce
lls, where they promote cell cycle progression and induce transcriptional a
ctivation of "immediate early" and cyclin genes. Nongenomic signaling by es
trogens, including rapid changes of mitogen-activated protein (MAP) kinase
and other signal-transduction-cascades activity, has been proposed to be es
sential for the mitogenic actions of these hormones and their nuclear recep
tors. Because regulation of gene transcription is considered a key step in
cell cycle control by mitogenic protein kinase cascades, here we investigat
ed the possibility that estrogen might induce the activation of extracellul
ar signal-regulated kinase (Erk) 1/2-, c-Jun NH2-terminal kinase-, p38- or
protein kinase A-responsive transcription factors in the cell nucleus durin
g stimulation of early G(1) progression, a timing coincident with the maxim
um effects of these hormones on such enzyme activity. No significant change
s in protein kinase-mediated transcription factor activity could be detecte
d here after estrogen stimulation of either MCF-7 or ZR-75.1 cells. Further
more, these steroids were able to induce activation of the human CCND1 gene
promoter, accumulation of cyclin D1 and pRb phosphorylation, all key event
s in cell cycle stimulation by mitogens, even in the presence of Erk1/2 act
ivation blockade by a MAP kinase-activating kinase (Mek)1/2 inhibitor. Thus
, estrogens do not appear to convey significant protein kinase-dependent si
gnaling to the cell nucleus during the early phases of human breast cancer
cell stimulation. Furthermore, hormonal regulation of G(1) gene transcripti
on can occur even without additional activation of the Mek-Erk1/2 pathway b
y estrogen receptors.