Downregulation of estrogen receptors by mitogenactivated protein kinases

Although, as established above, growth factor pathways can enhance ER phosphorylation, transcriptional activity and cell growth in a lig-and-independent manner, paradoxically a decline in ER expression is also a possible outcome when growth factor signaling is extreme or sustained. Evidence for this arises from several stable transfection studies in ER-positive breast cancer cells. Such studies demonstrate that growth factor signaling elements comprising the EGFR/HER2 pathway, which share an ability to hyperactivate ERK1/2 MAP kinase, all act to impair ER function and promote ER loss when overexpressed in ER-positive breast cancer cells. In our own laboratory, we have shown that constitutive upregulation of MEK1 in MCF-7 cells leads to a substantial increase in ERK1/2 MAP kinase activation, decreased ER level, and marked loss of expression of the ER-regulated gene progesterone receptor (PR) (RA McClelland, unpublished observations). Similarly, El-Ashry and colleagues39,40 have noted precipitous falls in ER mRNA and protein following transfection of constitutively active HER2, MEK1, Raf1 or ligand-stimulated EGFR into MCF-7 cells, all of which hyperactivate ERK1/2 MAPK. There is a parallel loss of estrogen-mediated gene expression and a marked suppression of activity of ERE-reporter gene constructs in these transient transfection experiments which is not overcome by estra-diol treatment. Increased ERK1/2 activity has also been reported to mediate hypoxia-induced ER downregulation, and ERK7 has been shown to regulate hormone responsiveness in breast cells by controlling the rate of ERa degradation.41,42 Holloway et al43 later demonstrated that hyperactivated ERK1 /2 MAPK is able to downregulate ER via substrates including the transcription factor nuclear factor kappa B (NFkB), which is markedly increased in activity in the various transfection models and is inhibited by abrogating ERK1/2 MAPK signaling.

Estrogens stimulate positive elements of growth factor signaling pathways, which may facilitate extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase-directed cell proliferation

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