Abstract
The estrogen receptor alpha (ERα) signaling plays an essential role in breast cancer progression and endocrine therapy. Mitogen-activated protein kinase (MAPK/Erk1/2) has been implicated in ligand-independent activation of ER, resulting in the cross-talk between growth factor and ER mediated signaling. In this study, we examined the effect of the cross-talk on estradiol (E2)-mediated signaling, tumor growth and its effect on anti-estrogen therapy. Our findings demonstrate that expression of constitutively activated mitogen activated kinase kinase (MEK1), an immediate upstream activator of MAPK in estrogen receptor positive MCF-7 breast cancer cells (MEK/MCF-7), showed an increase in ERα-driven transcriptional activation. In MEK/MCF-7 cells maximal transactivation levels were achieved in response to treatment with much lower E2 concentrations (10−10 M E2) when compared to MCF-7 control cells (10−8 M E2). Furthermore, we have seen an increased association between ERα and its nuclear coactivators AIB1 or TIF-2, in MEK/MCF-7 cells relative to those seen in MCF-7 control cells. In addition, in vivo studies show that MEK/MCF-7 cell tumors are ∼threefold larger than those of MCF-7 cell, in the presence of E2. Immunohistochemical staining demonstrates that progesterone receptor (PR) and pS2, two E2-regulated gene products, are significantly increased in MEK/MCF-7 cell tumors compared to those of MCF-7 control tumors, suggesting that activation of ERα by MAPK enhances the expression of E2-regulated genes and accelerates tumor growth. Remarkably, the antiestrogens tamoxifen and ICI 182,780, were shown both in vitro and in vivo studies to efficiently antagonize the stimulatory effects of E2 on ER regulated transactivation and tumor growth in MEK/MCF-7 as well as MCF-7 cell lines. Taken together, these data suggest that MAPK/ER cross-talk enhances ERα-mediated signaling and accelerates E2-dependent tumor growth without diminishing sensitivity to the inhibitory effects of anti-estrogens.
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Acknowledgements
We thank Dr Natalie Ahn (University of Colorado, Boulder, CO, USA) for providing activated MEK cDNA. This research is supported by funds from NIH grants (CA 64248 and CA 83964) to KB Reddy.
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Atanaskova, N., Keshamouni, V., Krueger, J. et al. MAP kinase/estrogen receptor cross-talk enhances estrogen-mediated signaling and tumor growth but does not confer tamoxifen resistance. Oncogene 21, 4000–4008 (2002). https://doi.org/10.1038/sj.onc.1205506
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DOI: https://doi.org/10.1038/sj.onc.1205506
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