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

Lombardi Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC 20007

Address all correspondence and requests for reprints to: Dorraya El-Ashry, Lombardi Cancer Center, Rm. W313, TRB, 3970 Reservoir Rd., NW, Washington, DC 20007. E-mail: elashryd{at}gunet georgetown.edu

ER-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 (raf) activity imparts ER- positive MCF-7 breast cancer cells with the ability to grow in the absence of estrogen. raf transfectants maintained in estrogen-depleted media showed greatly diminished responses to 17ß-estradiol or the pure antiestrogen ICI 182,780. Western blotting, ligand binding, and immunohistochemistry assays revealed a loss of ER protein expression, and ribonuclease protection assays indicated that this correlated with loss of ER 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 raf or constitutively active MAPK kinase (MEK), no ligand- independent activation of ER was observed. Transient expression of raf and double-label immunostaining showed ER was lost in those cells that transiently expressed raf. Abrogation of Raf signaling via treatment with the MEK inhibitors PD 098059 or U0126 resulted in reexpression of ER. Similar studies performed with MCF-7 cells overexpressing epidermal growth factor receptor or c-erbB-2 confirmed that hyperactivation of MAPK resulted in down-regulation of ER that was reversible by MEK inhibition or transfection with dominant negative ERK1 and ERK2 constructs. These data suggest that the hyperactivation of MAPK in epidermal growth factor receptor- or c-erbB-2-overexpressing breast cancer cells is directly responsible for generation of an ER-negative phenotype and, more importantly, that this process may be abrogated by inhibiting these pathways, thus restoring ER expression.

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