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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 375-383
Copyright © 2004 by The Endocrine Society

Differential Recruitment of Coregulator Proteins Steroid Receptor Coactivator-1 and Silencing Mediator for Retinoid and Thyroid Receptors to the Estrogen Receptor-Estrogen Response Element by ß-Estradiol and 4-Hydroxytamoxifen in Human Breast Cancer

Fergal J. Fleming, Arnold D. K. Hill, Enda W. McDermott, Niall J. O’Higgins and Leonie S. Young

Department of Surgery (F.J.F., A.D.K.H., E.W.M., N.J.O., L.S.Y.), St. Vincent’s University Hospital, and Conway Institute of Biomolecular and Biomedical Research (A.D.K.H., L.S.Y.), University College Dublin, Dublin 4, Ireland

Address all correspondence and requests for reprints to: L. S. Young, Department of Surgery, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland. E-mail: leonie.young{at}ucd.ie.

Estrogen receptor (ER)-{alpha} and ER-ß function as transcription factors, and both interact with nuclear regulatory proteins to enhance or inhibit transcription. We hypothesized that coregulators are expressed in breast cancer and may be differentially recruited by ERs in the presence of estrogen and tamoxifen. ER-ß was found to be expressed more frequently in node-negative patients (P < 0.05). Expression of steroid receptor coactivator-1 (SRC-1) was associated with nodal positivity (P < 0.05) and resistance to endocrine treatment (P < 0.001). The spatial coexpression of ER-{alpha}, ER-ß, and the coregulatory proteins was established using immunofluorescence. In both cell lines (MCF-7 and T47D) and in primary breast cancer cell cultures, ß-estradiol up-regulated ER-ß and coregulator protein expression and increased ER-{alpha}/ER-ß interaction with the estrogen response element (ERE). 4- Hydroxy-tamoxifen (4-OHT) increased ER-{alpha} and silencing mediator for retinoid and thyroid receptors (SMRT) expression and increased ER-ERE binding. SRC-1 and SMRT were identified at the ER-ERE complex, and interactions between ER isoforms and coregulatory proteins were determined using immunoprecipitation. Both ER-{alpha} and ER-ß preferentially bound SRC-1 in the presence of ß-estradiol. Conversely, in cells treated with 4-OHT, ER-{alpha} and ER-ß bound SMRT. Differential recruitment of SRC-1 and SMRT by ER-{alpha} and ER-ß in the presence of ß-estradiol and 4-OHT may be central to the response of the tumor to endocrine treatment.

F.J.F. is the Royal College of Surgeons in Ireland Surgical Research Fellow 2002–2003.

Abbreviations: AIB1, Amplified in breast cancer coactivator; ER, estrogen receptor; ERE, estrogen response element; 4-OHT, 4-hydroxytamoxifen; SERM, selective ER modulator; SMRT, silencing mediator for retinoid and thyroid receptors; SRC-1, steroid receptor coactivator-1.




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