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Research Articles: Therapeutics, Targets, and Development

Classification of anti-estrogens according to intramolecular FRET effects on phospho-mutants of estrogen receptor

Department of Tumor Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands

Requests for reprints: Rob Michalides, Division of Tumor Biology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands. Phone: 31-20-5122022; Fax: 31-205122029. E-mail: r.michalides{at}nki.nl

Abstract

Anti-estrogen resistance is a major clinical problem in the treatment of breast cancer. In this study, fluorescence resonance energy transfer (FRET) analysis, a rapid and direct way to monitor conformational changes of estrogen receptor (ER) upon anti-estrogen binding, was used to characterize resistance to anti-estrogens. Nine different anti-estrogens all induced a rapid FRET response within minutes after the compounds have liganded to ER in live cells, corresponding to an inactive conformation of the ER. Phosphorylation of Ser³⁰⁵ and/or Ser²³⁶ of ER by protein kinase A (PKA) and of Ser¹¹⁸ by mitogen-activated protein kinase (MAPK) influenced the FRET response differently for the various anti-estrogens. PKA and MAPK are both associated with resistance to anti-estrogens in breast cancer patients. Their respective actions can result in seven different combinations of phospho-modifications in ER where the FRET effects of particular anti-estrogen(s) are nullified. The FRET response provided information on the activity of ER under the various anti-estrogen conditions as measured in a traditional reporter assay. Tamoxifen and EM-652 were the most sensitive to kinase activities, whereas ICI-182,780 (Fulvestrant) and ICI-164,384 were the most stringent. The different responses of anti-estrogens to the various combinations of phospho-modifications in ER elucidate why certain anti-estrogens are more prone than others to develop resistance. These data provide new insights into the mechanism of action of anti-hormones and are critical for selection of the correct individual patient-based endocrine therapy in breast cancer. [Mol Cancer Ther 2007;6(5):1526–33]

Grant support: Dutch Cancer Organization, Koningin Wilhelmina Fonds 2005-3388.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

² W. Zwart et al., in preparation.

Received 12/ 5/06; revised 2/21/07; accepted 3/27/07.

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