Hyperactivation of MAPK Induces Loss of ERα Expression in Breast Cancer Cells

ERα-negative breast tumors tend to overexpress growth factor receptors such as epidermal growth factor receptor or c-erbB-2. Raf-1 is a key intermediate in the signal transduction pathways of these receptors. High levels of constitutive Raf kinase (Δraf) activity imparts ERα- positive MCF-7 breast cancer cells with the ability to grow in the absence of estrogen. Δraf transfectants maintained in estrogen-depleted media showed greatly diminished responses to 17β-estradiol or the pure antiestrogen ICI 182,780. Western blotting, ligand binding, and immunohistochemistry assays revealed a loss of ERα protein expression, and ribonuclease protection assays indicated that this correlated with loss of ERα message. In examining the basal expression of estrogen-induced genes in the stable transfectants or in transient cotransfection assays with an estrogen-response element- reporter construct and Δraf or constitutively active MAPK kinase (ΔMEK), no ligand- independent activation of ERα was observed. Transient express...