Serine-305 Phosphorylation Modulates Estrogen Receptor Alpha Binding to a Coregulator Peptide Array, with Potential Application in Predicting Responses to Tamoxifen

R Houtman, R (Renée) de Leeuw, M Rondaij, D Melchers, D Verwoerd, R Ruijtenbeek, John Martens, J Neefjes, R Michalides

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With current techniques, it remains a challenge to assess coregulator binding of nuclear receptors, for example, the estrogen receptor alpha (ER alpha). ER alpha is critical in many breast tumors and is inhibited by antiestrogens such as tamoxifen in cancer therapy. ER alpha is also modified by acetylation and phosphorylation that affect responses to the antiestrogens as well as interactions with coregulators. Phosphorylation of ER alpha at Ser305 is one of the mechanisms causing tamoxifen resistance. Detection of resistance in patient samples would greatly facilitate clinical decisions on treatment, in which such patients would receive other treatments such as aromatase inhibitors or fulvestrant. Here we describe a coregulator peptide array that can be used for high-throughput analysis of full-length estrogen receptor binding. The peptide chip can detect ER alpha binding in cell and tumor lysates. We show that ER alpha phosphorylated at Ser305 associates stronger to various coregulator peptides on the chip. This implies that ER alpha Ser305 phosphorylation increases estrogen receptor function. As this is also detected in a breast tumor sample of a tamoxifen-insensitive patient, the peptide array, as described here, may be applicable to detect tamoxifen resistance in breast tumor samples at an early stage of disease and contribute to personalized medicine. Mol Cancer Ther; 11(4); 805-16. (C) 2012 AACR.
Original languageUndefined/Unknown
Pages (from-to)805-816
Number of pages12
JournalMolecular Cancer Therapeutics
Issue number4
Publication statusPublished - 2012

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  • EMC MM-03-86-01

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