Protein kinase ERK7/8, a key regulator of estrogen receptor alpha

Approximately 50--60% of malignant breast tumors express the estrogen receptor alpha (ERalpha) at levels 10-fold or greater than those detected in normal breast tissue. The observed increase in ERalpha level is associated with estrogen hypersensitivity and enhanced tumor proliferation. Therefore, it is essential to understand the mechanisms that regulate total cellular ERalpha content. ERalpha turnover is regulated by the 26S proteasome, but the signaling pathways that modulate ERalpha degradation are unknown. Initially, we found that rat extracellular signal-regulated kinase 7 (ERK7) preferentially enhances proteasome-mediated degradation of ERalpha but not the related androgen receptor. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ERalpha degradation >4-fold in the presence of hormone, and potentiated estrogen responsiveness. Furthermore, an anti-ERK7 antibody recognized a protein of the correct relative molecular mass in human breast tissue, suggesting the presence of ERK7 in the human genome. Loss of human ERK7 was correlated with breast cancer progression. In addition, all ERalpha-positive breast tumors had decreased human ERK7 expression compared to normal breast tissue. We also found that ERK7 targets the ERalpha ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ERalpha turnover.; Our subsequent studies revealed that ERK7 is not present in the human genome. However, we demonstrate that ERK8 is a human homologue of rat ERK7. ERK8 and ERK7 share the unique identifier, Gln-138 in ERK8 and Gln-139 in ERK7. Similar to ERK7, ERK8 specifically enhanced the proteasome-mediated degradation of ERalpha. ERK8 increased endogenous ERalpha degradation in human breast cells and reduced ERalpha-mediated upregulation of the human progesterone receptor by ∼2 fold. The anti-ERK7 antibody recognized recombinant ERK8, suggesting that the protein originally detected in the human breast tissue specimens was ERK8. ERK8 transcripts were expressed equivalently in normal human breast cells and breast cancer cells, but the rate of ERK8 degradation was enhanced in breast cancer cells. These data show that ERK8 regulates ERalpha degradation and estrogen responsiveness in human breast cells. Loss of ERK8 expression, possibly by enhanced degradation of ERK8, may contribute to breast cancer progression.