Abstract
The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) and its more active isoform AIB1-Δ3 are overexpressed in breast cancer and preneoplastic breast tissue. However, the impact of these proteins on the transcriptional activity of natural estrogens or selective estrogen receptor modulators (SERMs) has not been determined. Here we show that AIB1-Δ3 causes a significant increase in the efficacy of 17β-estradiol at both estrogen receptor-α (ER-α) and ER-β in ovarian, breast and endometrial cancer cell lines. AIB1-Δ3 also significantly increased the efficacy of the natural estrogen genistein at both ER-α and ER-β, whereas AIB1 had no effect on either the potency or efficacy of genistein at either receptor. The estrogenic efficacy of the partial agonist tamoxifen was significantly increased in all cell lines at ER-α by overexpression of AIB1-Δ3 both on transfected and endogenous estrogen responsive genes. In contrast, overexpression of AIB1 or AIB1-Δ3 had no effect on the potency or efficacy of the SERM raloxifene. We conclude that overexpression of the AIB1-Δ3 isoform will increase the estrogenicity of a variety of natural and pharmacologic compounds in tissues that develop hormone-dependent neoplasias and overexpression of these cofactors may be a contributing factor to the hormone-driven development of neoplasia and to antiestrogen resistance of breast cancers.
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Acknowledgements
The authors thank Dr Kristina J Lauritsen for her erudite assistance with editing this manuscript. This work was supported by grants from the Breast Cancer Research Program of the Department of Defense awarded to ATR (DAMD17-99-1-9203), AO (DAMD17-02-1-0394) and with developmental funds from the Lombardi Cancer Center's SPORE in Breast Cancer (P50 CA58185) awarded to ATR.
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Reiter, R., Oh, A., Wellstein, A. et al. Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Δ3 on estrogenic ligands with different intrinsic activity. Oncogene 23, 403–409 (2004). https://doi.org/10.1038/sj.onc.1207202
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DOI: https://doi.org/10.1038/sj.onc.1207202