MAP kinase/estrogen receptor cross-talk enhances estrogen-mediated signaling and tumor growth but does not confer tamoxifen resistance

The estrogen receptor alpha (ERalpha) 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 (E-2)-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 ERalpha-driven transcriptional activation. In MEK/MCF-7 cells maximal transactivation levels were achieved in response to treatment with much lower E-2 concentrations (10(10) M E-2) when compared to MCF-7 control cells (10(8) M E-2) Furthermore, we have seen an increased association between ERalpha and its nuclear coactivators AIB1 or TIF2, 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 similar tothreefold larger than those of MCF-7 cell, in the presence of E-2. Immunohistochemical staining demonstrates that progesterone receptor (PR) and pS2, two E-2-regulated gene products, are significantly increased in MEK/MCF-7 cell tumors compared to those of MCF-7 control tumors, suggesting that activation of ERalpha by MAPK enhances the expression of E-2-regulated genes and accelerates tumor growth. Remarkably, the antiestrogens tamoxifen and ICI 182,780, were shown both in vitro and in giro studies to efficiently antagonize the stimulatory effects of E-2 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 ERalpha-mediated signaling and accelerates E-2-dependent tumor growth without diminishing sensitivity to the inhibitory effects of anti-estrogens.