Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Δ3 on estrogenic ligands with different intrinsic activity

Reiter, Ronald; Oh, Annabell S.; Wellstein, Anton; Riegel, Anna T.

doi:10.1038/sj.onc.1207202

Cited by 46 publications

(27 citation statements)

References 36 publications

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“…This increase in transcription is most likely due to a relief of repression of the endogenous AIB1 in the COS-7 cells because we are able to detect endogenous AIB1 protein by Western blot (17). Previous studies from our group and others have suggested that the N-terminal region containing the bHLH and PAS A domains contains an inhibitory domain that represses activity in both the nucleus and cytoplasm (17,18,21,26,36). Our studies and those from Chen et al (36) have shown that the loss of the N-terminal region leads to potent coactivation of nuclear hormone receptor-mediated transcription.…”

Section: Discussionmentioning

confidence: 72%

“…AIB1-⌬4 mRNA expression was elevated in breast tumor tissue relative to normal breast tissue (17). It was also shown to increase the efficacy of estrogenic compounds and the agonist effects of the selective estrogen receptor modulator tamoxifen in breast and endometrial tumor cells (17,18). Overexpression of AIB1-⌬4 in mice leads to ductal ectasia in the mammary gland with an increased expression of proliferative markers such as proliferating cell nuclear antigen, phospho-histone H3, and cyclin D1 (19) as well as increased cross-talk with ER␣ 2 in epithelial and stromal responses (20).…”

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confidence: 99%

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Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

Chien

Kirilyuk

et al. 2011

Journal of Biological Chemistry

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The oncogene amplified in breast cancer 1 (AIB1) is a nuclear receptor coactivator that plays a major role in the progression of various cancers. We previously identified a splice variant of AIB1 called AIB1-⌬4 that is overexpressed in breast cancer. Using mass spectrometry, we define the translation initiation of AIB1-⌬4 at Met 224 of the full-length AIB1 sequence and have raised an antibody to a peptide representing the acetylated N terminus. We show that AIB1-⌬4 is predominantly localized in the cytoplasm, although leptomycin B nuclear export inhibition demonstrates that AIB1-⌬4 can enter and traffic through the nucleus. Our data indicate an import mechanism enhanced by other coactivators such as p300/CBP. We report that the endogenously and exogenously expressed AIB1-⌬4 is recruited as efficiently as full-length AIB1 to estrogen-response elements of genes, and it enhances estrogen-dependent transcription more effectively than AIB1. Expression of an N-terminal AIB1 protein fragment, which is lost in the AIB1-⌬4 isoform, potentiates AIB1 as a coactivator. This suggests a model whereby the transcriptional activity of AIB1 is squelched by a repressive mechanism utilizing the N-terminal domain and that the increased coactivator function of AIB1-⌬4 is due to the loss of this inhibitory domain. Finally, we show, using Scorpion primer technology, that AIB1-⌬4 expression is correlated with metastatic capability of human cancer cell lines.Gene transcription in eukaryotes is a complex and highly regulated process. One of the major controls of gene transcription is exerted by the coregulator family of proteins. These include both corepressors, which dampen transcription, and coactivators, which potentiate transcription. A subgroup of coactivators has been shown to be critical for the malignant progression of cancer and is known as the p160 steroid receptor coactivators (1). One member in particular was identified to be amplified in breast cancer. Amplified in breast cancer 1 (AIB1, SRC-3, NCOA3, ACTR, TRAM-1, pCIP, and RAC3) has been shown to be a gene amplified in breast cancer (2) and is also overexpressed at the mRNA and protein level in various cancers (1, 3, 4). Its role in tumorigenesis is attributed to its ability to coactivate both steroid hormone-and growth factor-dependent transcription (3, 5-7). In several oncogene-driven mouse models (8 -11), reduction of AIB1 levels leads to a decrease in tumorigenesis, and overexpression of AIB1 leads to the formation of various tumors (12). Clinically, AIB1 expression in breast cancer cases is correlated with high HER2 levels, larger tumor size, higher tumor grade, and shorter disease-free survival (13-15). Also, high levels of AIB1 in conjunction with high HER2 levels coincide with reduced disease-free survival in patients treated with tamoxifen, suggesting a role for AIB1 in tamoxifen resistance (16).We had previously identified a splice variant of AIB1, where exon 3 was spliced from the mature mRNA and the resulting protein named AIB1-⌬3 (17). More recently, an additio...

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Section: Discussionmentioning

confidence: 72%

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confidence: 99%

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

Chien

Kirilyuk

et al. 2011

Journal of Biological Chemistry

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“…Furthermore, AIB1 is rate-limiting for estrogen-mediated growth of MCF-7 human breast cancer cells (14). AIB1 gene expression is up-regulated by selective ER modulators, such as tamoxifen (15) and the estrogenic activity of selective ER modulators, can be increased by AIB1 and an AIB1 isoform (16). However, emerging data suggest that the role of AIB1 is not restricted to nuclear receptor signaling.…”

Section: Introductionmentioning

confidence: 91%

The Nuclear Receptor Coactivator AIB1 Mediates Insulin-like Growth Factor I-induced Phenotypic Changes in Human Breast Cancer Cells

Oh¹,

List²,

Reiter³

et al. 2004

Cancer Research

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The nuclear receptor coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent antianoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-Istimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signalregulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen receptor signaling.

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“…Several mechanisms have been proposed to explain why tamoxifen may act as an antagonist in some tissues and act as an agonist in others, including cell-specific tamoxifen-induced changes in ERa conformation or modifications that alter the ability of ERa to interact with coactivators or corepressors, expression levels of coactivators or corepressors, or activity of other intracellular signaling pathways (Dutertre and Smith, 2000;Graham et al, 2000;McDonnell et al, 2002;Heldring et al, 2004;Jordan, 2004;Smith and O'Malley, 2004). The agonist activity of tamoxifen is increased when the coactivator AIB1/SRC-3 or its isoform AIB1-D3 is overexpressed (Reiter et al, 2004) and tamoxifen increases steady-state protein levels of SRC-1 and AIB1/SRC-3 (Lonard et al, 2004). Higher levels of AIB1 expression in human breast cancer have been associated with poorer outcome following tamoxifen therapy .…”

Section: Discussionmentioning

confidence: 99%

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Jones

Halama

et al. 2005

Oncogene

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Loss of full-length Brca1 in mammary epithelial cells of the mouse mammary tumor virus (MMTV)-Cre Brca1 conditional exon 11 deletion mouse model results in the development of mammary adenocarcinomas with similar genetic changes to those found in human BRCA1-mutation-related breast cancers. We used this experimental model to evaluate the chemopreventive effect of tamoxifen on the development of mammary preneoplasia and adenocarcinoma. No protective effects of tamoxifen administration on mammary cancer development were found. Instead, tamoxifen treatment significantly increased rates of mammary epithelial cell proliferation and the prevalence of mammary hyperplasia at 6 months of age. Tamoxifen-exposed mice developed adenocarcinomas at younger ages than control mice and a higher percentage of mice developed adenocarcinomas by 12 months of age. Both whole mouse and tissue culture cell models were used to test if loss of full-length Brca1 was associated with a relative increase in the agonist activity of tamoxifen. Tamoxifen induced increased ductal growth in MMTV-Cre Brca1 conditional mice compared to wild type. Estrogen receptor alpha (ERa) expression was downregulated in the tamoxifen-induced hyperplasias. Reducing BRCA1 levels in MCF-7 cells using siRNA resulted in a relative increase in the agonist activity of tamoxifen. Results suggest a model of mammary cancer progression in which loss of full-length Brca1 altered the agonist/antagonist activity of tamoxifen, resulting in tamoxifen-induced mammary epithelial cell proliferation with subsequent loss of ERa expression and development of ERa-negative hyperplasias and adenocarcinomas.

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Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Δ3 on estrogenic ligands with different intrinsic activity

Cited by 46 publications

References 36 publications

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

Role of the Nuclear Receptor Coactivator AIB1-Δ4 Splice Variant in the Control of Gene Transcription

The Nuclear Receptor Coactivator AIB1 Mediates Insulin-like Growth Factor I-induced Phenotypic Changes in Human Breast Cancer Cells

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

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