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A Cytoplasmic Substrate of Mitogen-Activated Protein Kinase Is Responsible for Estrogen Receptor- Down-Regulation in Breast Cancer Cells: The Role of Nuclear Factor-B

Lombardi Cancer Center (J.N.H.), Georgetown University, Washington, D.C. 20007; and University of Michigan Comprehensive Cancer Center (S.M., D.E.-A.), Ann Arbor, Michigan 48109-0640

Address all correspondence and requests for reprints to: Dorraya El-Ashry, University of Michigan Comprehensive Cancer Center, 1150 West Medical Center Drive, MSRB III, Room 5220B/5323, Ann Arbor, Michigan 48109-0640. E-mail: elashryd{at}umich.edu.

Estrogen receptor (ER) negative breast tumors often present with enhanced expression and/or activation of growth factor receptors, resulting in increased growth factor signaling and hyperactivation of MAPK (ERK1 and ERK2). We have pre-viously shown that ER(+) MCF-7 cells with elevated growth factor signaling lose expression of ER without any ligand-independent transcriptional activation, and this is a reversible effect attributable to ERK1/2 hyperactivation. Here, we show that down-regulation of ER is not mediated by a specific ERK-1 vs. ERK-2 substrate. Despite up-regulated activator protein-1 activity in response to ERK1/2 activation, and in ER(–) and hormone-independent breast cancers, we find that increased activator protein-1 activity is not responsible for ER down-regulation. Interestingly, our findings implicate a cytoplasmic substrate of ERK1/2. However, RSK1, the best-characterized cytoplasmic ERK1/2 substrate, does not down-regulate ER in our models. On the other hand, inhibition of nuclear factor-B (which is linked to chemoresistance in cancer in general and has elevated activity in hormone-independent and ER– breast cancer) significantly enhances ER activity, suggesting that indirect elevation in nuclear factor-B activity (due to hyperactive ERK1/2) is at least partially responsible for ER down-regulation in these cell line models.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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