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Submitted on July 12, 2005
Accepted on January 25, 2006
Department of Pathology, Department of Physiology, Wayne State University School of Medicine, The Barbara Ann Karmanos Cancer Institute, 540 East Canfield, Detroit, MI-48201, USA
* To whom correspondence should be addressed. E-mail: kreddy{at}med.wayne.edu.
The antiestrogen tamoxifen is widely used as selective estrogen receptor modulator for estrogen receptor alpha (ER)-positive breast tumors for decades. 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 family members, EGFR and ErbB2. In this report we now show that over expression of EGFR or activated AKT-2 in MCF-7 cells leads to phosphorylation of Ser167 in the AF-1 domain of ER
, enhanced ER:AIB1 interaction in the presence of Tam, and resistance to tamoxifen. In contrast, transfection of activated MEK, an immediate upstream activator of mitogen activated protein kinase (MAPK/Erk1&2) into MCF-7 cells leads to phosphorylation of Ser118 in the AF-1 domain of ER, inhibition of ER:AIB1 interaction in the presence of Tam, and maintenance of sensitivity to tamoxifen. Inhibition of AKT by siRNA 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.
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