Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Delta3 on estrogenic ligands with different intrinsic activity.
The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) and its more active isoform AIB1-Delta3 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-Delta3 causes a significant increase in the efficacy of 17beta-estradiol at both estrogen receptor-alpha (ER-alpha) and ER-beta in ovarian, breast and endometrial cancer cell lines. AIB1-Delta3 also significantly increased the efficacy of the natural estrogen genistein at both ER-alpha and ER-beta, 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-alpha by overexpression of AIB1-Delta3 both on transfected and endogenous estrogen responsive genes. In contrast, overexpression of AIB1 or AIB1-Delta3 had no effect on the potency or efficacy of the SERM raloxifene. We conclude that overexpression of the AIB1-Delta3 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.
Reiter
Ronald
R
Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
Oh
Annabell S
AS
Wellstein
Anton
A
Riegel
Anna Tate
AT
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D056921:Nuclear Receptor Coactivator 3; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D014157:Transcription Factors; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D019833:Genistein; D056921:Nuclear Receptor Coactivator 3