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Activation Function-1 Domain of Estrogen Receptor Regulates the Agonistic and Antagonistic Actions of Tamoxifen

Departments of Pathology (S.G., N.A., K.B.R.) and Physiology (C.Z., D.F.S.), Wayne State University School of Medicine, The Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201

Address all correspondence and requests for reprints to: Kaladhar B. Reddy, Department of Pathology, Wayne State University, 540 East Canfield Avenue, Detroit, Michigan 48201. E-mail: kreddy{at}med.wayne.edu.

The antiestrogen tamoxifen has been widely used for decades as selective estrogen receptor (ER) modulator for ER-positive breast tumors. Tamoxifen significantly reduces tumor recurrence by binding to the activation function-2 (AF-2) domain of the ER. Acquired resistance to tamoxifen in breast cancer patients is a serious therapeutic problem. Antiestrogen-resistant breast cancer often shows increased expression of the epidermal growth factor receptor (EGFR) family members, EGFR and ErbB2. In this report we now show that overexpression of EGFR or activated AKT-2 in MCF-7 cells leads to phosphorylation of Ser167 in the AF-1 domain of ER, enhanced ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of tamoxifen, and resistance to tamoxifen. In contrast, transfection of activated MAPK kinase, an immediate upstream activator of MAPK (ERK 1 and 2) into MCF-7 cells leads to phosphorylation of Ser118 in the AF-1 domain of ER, inhibition of ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of Tam, and maintenance of sensitivity to tamoxifen. Inhibition of AKT by short inhibitory RNA blocked Ser167 phosphorylation in ER and restored tamoxifen sensitivity. However, maximum sensitivity to tamoxifen was observed when both AKT and MAPK were inhibited. Taken together, these data demonstrate that different phosphorylation sites in the AF-1 domain of ER regulate the agonistic and antagonistic actions of tamoxifen in human breast cancer cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   AIB1

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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