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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In human breast carcinomas, increased copy number of DNA sequences derived from the long arm of chromosome 20 (20q) has been commonly observed by both chromosome microdissection and comparative genomic hybridization. This chromosomal region is likely to contain one or more genes that are the biological targets of this amplification event. We describe here the utilization of a chromosome microdissection-hybrid selection strategy to isolate transcribed sequences from microdissected homogeneously staining regions encompassing 20q. Using this strategy, we have isolated three novel amplified genes (termed AIB1, AIB3, and AIB4) from a cDNA library constructed from the 20q amplified breast cancer cell line BT-474. These three genes were mapped to 20q11 (AIB3 and AIB4) and 20q12 (AIB1) by fluorescence in situ hybridization. Our results indicate an unsuspected complexity to the amplification pattern of 20q in breast cancer and provide probes that will be useful for further characterization of tumor specimens.
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PMID:Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer. 875 10

Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number were elevated in human breast cancers. AIB1 amplification and overexpression were observed in four of five estrogen receptor-positive breast and ovarian cancer cell lines. Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed. AIB1 protein interacted with estrogen receptors in a ligand-dependent fashion, and transfection of AIB1 resulted in enhancement of estrogen-dependent transcription. These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers.
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PMID:AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. 925 29

Nuclear receptors regulate transcription by binding to specific DNA response elements of target genes. Herein, we report the molecular cloning and characterization of a novel Xenopus cDNA encoding a transcription coactivator xSRC-3 by using retinoid X receptor (RXR) as a bait in the yeast two-hybrid screening. It belongs to a growing coactivator family that includes a steroid receptor coactivator amplified in breast cancer (AIB1), p300/ CREB-binding protein (CBP)-interacting protein (p/ CIP), and transcriptional intermediate factor 2 (TIF2). It also interacts with a series of nuclear receptors including retinoic acid receptor (RAR), thyroid hormone receptor (TR), and orphan nuclear receptors [hepatocyte nuclear receptor 4 (HNF4) and constitutive androstane receptor (CAR)]. However, it does not interact with small heterodimer partner (SHP), an orphan nuclear receptor known to antagonize ligand-dependent transactivation of other nuclear receptors. In CV-1 cells, cotransfection of xSRC-3 differentially stimulates ligand-induced transactivation of RXR, TR, and RAR in a dose-dependent manner. Interestingly, xSRC-3 is highly expressed in adult liver and early stages of oocyte development, suggesting that studies of xSRC-3 may lead to better understanding of the roles nuclear receptors play in oocyte development as well as liver-specific gene expression.
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PMID:Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2. 965 7

The AIB1 gene was isolated upon microdissection of the homogeneously staining regions observed in breast cancer cell lines. It was subsequently shown to map at a region at 20q12 that is frequently amplified in breast tumors. In a screen of breast tumor cell lines, of all the genes mapping to the region, AIB1 appeared to be the most consistently amplified and overexpressed. AIB1 shares homology with the SRC-1 family of nuclear receptor coactivators. It was found to interact in a ligand-dependent manner with the estrogen receptor (ER) and to result in increased levels of estrogen-dependent transcription. These properties could be of important biological significance in breast and ovarian cancerigenesis, and we were, therefore, interested in determining whether the amplification of the AIB1 gene was associated with a particular phenotype or subgroup in these tumors. We tested a population of 1157 breast and 122 ovarian tumors in which DNA amplification had been determined previously at 15 chromosomal locations. Amplification of the AIB1 gene was observed in 4.8% of breast cancers and 7.4% of ovarian cancers. In breast tumors, AIB1 was correlated with ER and progesterone receptor positivity, as well as with tumor size. Correlation was also observed with the amplification of MDM2 and FGFR1 genes, but interestingly, no correlation was found with the amplification of CCND1, which is known to be strongly associated with ER. Furthermore, analyzing at 20q12-q13 range, we show the existence of three amplification cores, represented by AIB3/AIB4, AIB1, and RMC20C001. AIB1 and CCND1 amplifications may, thus, represent two different subsets of ER-positive breast tumors.
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PMID:In breast cancer, amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity. 986 2

Some of the recently identified coactivators which interact with members of nuclear hormone receptors contain a stretch of homopolymeric glutamines (poly-Q). Length of poly-Q in several genes are known to be polymorphic in healthy subjects, and extraordinary expansion of poly-Q in specific genes is known to cause neurodegenerative disorders. In the present study, we investigated whether such polymorphism can be observed in two coactivators, CBP (CREB [cyclic AMP responsive element binding protein]-binding protein) and AIB1/ACTR (amplified in breast cancer-1/ACTR, also called RAC3/TRAM-1). The genomic regions encoding the poly-Q were amplified by means of PCR using fluorescence labeled primer and analyzed by an automatic sequencer. While contiguous glutamine residues inAIB1/ACTR ranged from 26 to 32 with a heterozygosity of 54%, no polymorphism could be observed in poly-Q of CBP among 54 unrelated subjects. These results suggest that the residue in CBP may play a critical role in the function so that individuals with CBP containing different sizes of poly-Q might have been eliminated. It has been reported that AIB1/ACTR is overexpressed in some of the cell lines derived from breast cancer. If the length of poly-Q alters the stability of AIB1/ACTR and/or potency to enhance hormone action through nuclear receptors, the length of poly-Q is likely to be one of the genetic factors affecting not only susceptibility to breast cancers but also the sensitivity to hormones. This polymorphism should also be tested in patients with neurodegenerative disorders of unknown cause.
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PMID:Polymorphism of homopolymeric glutamines in coactivators for nuclear hormone receptors. 1046 12

The steroid coactivator AIB1 (Ampified In Breast cancer 1) is a member of the SRC-1 family of transactivation coactivators that is amplified in about 7% of breast tumor samples. Hybridomas were established that secreted monoclonal antibodies (MAbs) to a recombinant glutathione-S-transferase (GST) fusion protein expressing the steroid receptor interacting domain of AIB1 (GST-AIB.T1:a.a. 605-1294). Four MAbs from these hybridomas were characterized and designated AX15.1, AX15.2, AX15.3, and AX15.4. The MAbs were shown to be specific to AIB1 and did not cross-react with two similar coactivators SRC-1 and TIF2 as shown in Western blot analysis and enzyme-linked immunoadsorbent assay (ELISA). Western blot analysis using the four MAbs showed specific recognition of AIB1 protein as a 160 kDa band in lysates from cell lines containing AIB1 gene-amplification. The MAbs immunoprecipitated in vitro-translated AIB1 and cellular AIB1 from metabolically labeled cells. The results show that these newly described MAbs are useful in studies of AIB1 function and expression.
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PMID:Production and characterization of monoclonal antibodies to the steroid receptor coactivator AIB1. 1047 43

The tumor suppressor protein p53 exerts its cell cycle-regulatory effects through its ability to function as a sequence-specific DNA-binding transcription factor. Herein, we show that p53 physically interacts with specific subregions of steroid receptor coactivator-1 (SRC-1) and its family members, p/CIP (p300/CBP interacting protein), xSRC-3, and AIB1 (amplified in breast cancer), originally isolated as transcription coactivators of nuclear receptors, as demonstrated by the yeast and mammalian two-hybrid tests as well as glutathione S-transferase pull-down assays. Interestingly, cotransfection of HeLa cells with SRC-1- or p/CIP expression vector potentiated the p53-mediated transactivation, whereas AIB1 and xSRC-3 were repressive. All of these SRC-1 members, however, similarly stimulated transactivation mediated by nuclear receptors and AP-1, as previously described. These results suggest that SRC-1 and its family members may differentially modulate the p53 transactivation in vivo.
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PMID:Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. 1055 85

In order to approach the molecular basis of the tissue-specific agonistic activity of antioestrogens, we have compared, at the mRNA level, the expression of various transcriptional cofactors (activators or repressors) of estrogen receptors in different breast (MCF7, ZR75-1, T47D, MDA-MB231) and endometrial (Ishikawa, RL-95-2 and HEC1A) human cancer cell lines. We showed that for SRC-1, CBP, TIF1alpha, RIP140, N-CoR, and SMRT, no significant differences in the expression levels were observed between breast and endometrial cells. For TIF1alpha mRNA, both isoforms were also detected at similar levels in all the cells tested. By contrast, over-expression of AIB1 mRNA was observed in MCF7 cells, but not in other breast or endometrial cells, irrespective of their ER-status. We then used protein-protein interaction assay (far-Western blot) to confirm the increased expression of at least one of the p160 proteins in MCF7 cells. Finally, we demonstrated that RIP140 mRNA is directly induced by estrogens in ER-positive MCF7 breast cancer cell lines but not in Ishikawa endometrial cells. Together these results indicate that some differences exist between breast and endometrial cancer cell lines at the level of estrogen receptor transcription cofactor expression.
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PMID:Estrogen receptor cofactors expression in breast and endometrial human cancer cells. 1061 26

Recent studies have indicated that a complex machinery of transactivation of target genes by estrogen or antiestrogen through estrogen receptor (ER) exists. However, the substantial roles of ER-beta, coactivators, and corepressors in the development and progression of breast cancer remain to be elucidated. To obtain some clue to these roles, we screened the expression levels of ER-alpha, ER-beta, coactivators (SRC-1, TIF2, AIB1, CBP, and P/CAF) and corepressors (N-CoR and SMRT) in 6 normal mammary glands, 6 intraductal carcinomas, 22 invasive ductal carcinomas, and 7 breast cancer cell lines using a multiplex reverse transcription-PCR. ER-alpha mRNA expression levels significantly correlated with ER-alpha protein levels measured by enzyme immunoassay in the breast cancer tissues and cell lines. A significant correlation of expression levels was observed between ER-alpha and TIF2, AIB1, P/CAF, and N-CoR, and between ER-beta and AIB1 and CBP in the tissue samples. A significant correlation was also observed between ER-alpha and ER-beta and between ER-beta and CBP in the cell lines. The expression levels of ER-alpha, TIF2, and CBP were significantly higher in the intraductal carcinomas than those in the normal mammary glands. In addition, the expression levels of ER-alpha and N-CoR were significantly higher in the intraductal carcinomas than those in the invasive ductal carcinomas. These findings suggest a positive correlation of expression levels among ER-alpha and cofactors and among ER-beta and cofactors, an up-regulation of expression levels of ER-alpha and cofactors during the development of intraductal carcinomas from normal mammary glands, and a decrease in their expression levels during the progression of breast cancer.
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PMID:Expression levels of estrogen receptor-alpha, estrogen receptor-beta, coactivators, and corepressors in breast cancer. 1069 May 32

Breast cancer heterogeneity can be related directly to its variability at the genetic level. Thus, tumor genotyping could be a valuable approach to define breast tumor subtypes. It has been shown that it is possible to delineate subgroups of breast tumors according to specific sets of DNA amplifications. The aim of the present work was to study the prognostic significance of these DNA amplifications. We studied DNA amplification at eight genes or loci (AIB1, CCND1, EMS1, ERBB2, FGFR1, MDM2, MYC, and RMC20C001) as well as p53 mutations in a series of 640 breast cancer patients who had not received presurgical therapy and analyzed the correlations with survival DNA amplification was assessed by Southern blotting and was scored positive when exceeding three to five copies. Mutations in the p53 gene were searched by four-color fluorescent single. strand conformational polymorphism, using an automated sequencer. Of the nine genetic alterations tested, four (CCND1, EMS1, FGFR1, and p53 mutations) showed a significant association with reduced disease-free (DFS) and/or overall survival (OVS) in the unselected set of patients by univariate test. Correlations for p53 were found only when selecting mutations in exons 5 or 7. Analysis of node-negative and -positive subgroups of patients showed that MDM2 amplification and p53 mutations bore prognostic significance in node-negative patients, whereas amplification of CCND1, EMS1, and FGFR1 correlated with poor outcome in node-positive patients. Multivariate analysis on an unselected set of patients retained significance for the amplification of EMS1, FGFR1, and MDM2 with DFS, of CCND1 with OVS, and of RMC20C001 with both DFS and OVS. Interestingly, stratified analysis according to nodal status confirmed results obtained in the univariate tests: significance of MDM2 amplification and p53 mutations in node-negative and that of CCND1, EMS1, and FGFR1 in node-positive patients. We also observed an association between the number of genetic alterations observed in a tumor and poor prognosis. Patients with two or more amplified loci had a worsened outcome. Strongly correlating coamplifications such as CCND1 and FGFR1, as well as ERBB2 and MYC, were associated with a significant reduction of patient survival, thus indicating cooperative effects. Our data support the idea that genetic alterations in breast cancer are not only helpful for phenotyping purposes, but can also represent powerful prognostic indicators in the clinical practice.
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PMID:Relating genotype and phenotype in breast cancer: an analysis of the prognostic significance of amplification at eight different genes or loci and of p53 mutations. 1070 27


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