Overexpression of the Nuclear Receptor Coactivator 
 AIB1
 (
 SRC-3
 ) during Progression of Pancreatic Adenocarcinoma

Henke, Ralf T.; Haddad, Bassem R.; Kim, Sung Eun; Rone, Janice D.; Mani, Aparna; Jessup, J. Milburn; Wellstein, Anton; Maitra, Anirban; Riegel, Anna T.

doi:10.1158/1078-0432.ccr-04-0561

Cited by 109 publications

(83 citation statements)

References 34 publications

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“…Genetic ablation of AIB1 inhibits spontaneous prostate cancer progression in mice (Chung et al, 2007), indicating that AIB1 has a role in promotion of prostate cancer progression. Several other studies showed that AIB1 is overexpressed in human colon, pancreas and stomach cancers and may contribute to the development of metastases (Sakakura et al, 2000;Henke et al, 2004;Xie et al, 2005). These results indicate that AIB1 is a bona fide oncogene.…”

Section: Introductionmentioning

confidence: 64%

Overexpression of transcriptional coactivator AIB1 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness

Chen

et al. 2010

Oncogene

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Amplified in breast cancer 1 (AIB1) is a transcriptional coactivator for nuclear receptors and other transcription factors. AIB1 has an important role in malignancy of several cancers such as breast and prostate cancers. However, its involvement in human hepatocellular carcinoma (HCC) progression remains unclear. Here, we found that AIB1 protein was overexpressed in 23 of 34 human HCC specimens (68%). Down-regulation of AIB1 reduced HCC cell proliferation, migration, invasion, colony formation ability and tumorigenic potential in nude mice. These phenotypic changes caused by AIB1 knockdown correlated with increased expression of the cell cycle inhibitor p21Cip1/Waf1 and decreased Akt activation and the expression of proliferating cell nuclear antigen (PCNA) and matrix metallopeptidase MMP-9. In agreement with these findings, clinical AIB1-positive HCC expressed higher levels of PCNA than AIB1-negative HCC. A positive correlation was established between the levels of AIB1 protein and PCNA protein in HCC, suggesting that AIB1 may contribute to HCC cell proliferation. In addition, MMP-9 expression in AIB1-postive HCC was significantly higher than that in AIB1-negative HCC, suggesting that AIB1-postive HCC may be more invasive. Collectively, our results show that overexpression of AIB1 promotes human HCC progression by enhancing cell proliferation and invasiveness. Therefore, AIB1 is a master regulator of human HCC growth and might be a useful molecular target for HCC prognosis and treatment.

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Section: Introductionmentioning

confidence: 64%

Overexpression of transcriptional coactivator AIB1 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness

Chen

et al. 2010

Oncogene

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“…Given that we have found that the expression of AIB1-⌬4 at the protein level is higher in breast and pancreatic cancer cells (17,61), we were interested to investigate if AIB1-⌬4 is regulated at the protein level. We have previously shown that AIB1 protein levels are greatly reduced in response to growth of cells at high confluence and the removal of growth factors (62).…”

Section: Discussionmentioning

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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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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“…In both Western blotting and immunocytochemical analysis, the SRC-1 antibody was used at 1:200, and the TIF2 and TRAM-1 antibodies were used at 1:150. These antibodies have previously been used successfully for immunohistochemistry and/or Western-blot analysis (23,26,27).…”

Section: Antibodiesmentioning

confidence: 99%

“…The monoclonal antibodies for three coactivators used in the present study were previously characterized to serve as valid probes (23,26,27,32). In fact, the Western blotting of cellular extracts from rat testis using each antibody detected a major 160 kDa band (Fig.…”

Section: Specificity Of Antibodiesmentioning

confidence: 99%

“…The vasoprotective functions of estrogen after vascular injury are also partially impaired (20). In addition, TRAM-1 was amplified and/or overexpressed in breast cancers, ovarian cancers (6), endometorial cancers (21), pancreatic cancers (22,23), gastric cancers (24), and prostate cancers (25), indicating that TRAM-1 is required for normal somatic growth and may play a role in oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of p160 steroid receptor coactivators in the rat testis and epididymis

et al. 2005

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Objective: Androgens are critical for the development and maintenance of male sexual characteristics. Their action is mediated through the androgen receptor (AR). Ligand-bound AR interacts with coactivator proteins that mediate transcriptional activation. Such coactivators include three members of the 160 kDa proteins (p160s): SRC-1, TIF2/GRIP1, and p/CIP/RAC3/ACTR/AIB1/TRAM-1. The aim of this study was to investigate the expression of the three p160 coactivators and their association with AR in testis and epididymis. Methods: We determined the localization of these three p160 coactivators in immature and mature rat testis, and epididymis by immunohistochemistry using the specific monoclonal antibodies. We also performed double immunofluorescence staining to examine whether p160s are colocalized with AR in these tissues. Results: In seminiferous tubules of mature rat testis, SRC-1 and TRAM-1 immunoreactivity was found predominantly in spermatogonia and spermatocytes. In contrast, TIF2 was expressed predominantly in Sertoli cells. AR was coexpressed with TIF2 in this cell type. In immature rat testis, however, all three coactivators were expressed in both germ cells and Sertoli cells. In the epididymis, SRC-1 and TIF2 immunoreactivities were localized in nuclei of epithelial cells. However, TRAM-1 immunostaining was observed in the luminal portion of the cytoplasm with greater intensity than in the nucleus, especially in the caput epididymidis. Conclusions: The cell-type-specific expression of p160 coactivators suggests specific roles in male reproductive organs. Further, the strong cytoplasmic localization of TRAM-1 protein in epithelial cells of epididymis suggests that TRAM-1 may have additional role(s) in transcriptional regulation.European Journal of Endocrinology 153 595-604

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Overexpression of the Nuclear Receptor Coactivator AIB1 ( SRC-3 ) during Progression of Pancreatic Adenocarcinoma

Cited by 109 publications

References 34 publications

Overexpression of transcriptional coactivator AIB1 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness

Overexpression of transcriptional coactivator AIB1 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness

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

Differential expression of p160 steroid receptor coactivators in the rat testis and epididymis

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