AIB1 Gene Research Articles

Genetic variation among einkorn genotypes based on gene targeted functional markers and its possible relationship with drought tolerance at seed germination stage.

Einkorn wheat is one of the first primary genetic resources for discovery of new alleles related to biotic and abiotic stress tolerances for further genetic improvements while it became more popular especially for its native grain status as healthy food resources. Therefore, this study aims to determine germination parameters of 32 local einkorn (Triticum monococcum) genotypes collected from Kastamonu and its vicinity, Turkey under drought stress conditions, and to reveal the genetic relationship of those genotypes based on drought related gene targeted functional markers (GTFMs). Germination test was conducted at 20 ± 0.5°C in darkness with randomized complete block design with 4 replications. Seeds placed on double filter papers in a covered glass petri dishes (80 × 15mm) were treated with polyethylene glycol (PEG6000) with a -0.23MPa. The final germination percentages (FGPs), speed and span of germination parameters were determined. Drought stress severely worsened all germination parameters measured. The genotypes SG24 and SG12 were the most drought tolerant and sensitive genotypes based on 21.1% and 64.8% of reduction rates in FGPs, respectively. Twelve GTFMs produced a total of 32 bands and 26 of them were polymorphic. The mean polymorphism ratio of the markers and average band per marker were determined as 86.31% and 2.66, respectively. The highest polymorphism information content (PIC) was obtained from AIB1 gene marker (0.875). This study revealed that there was a significant genetic variation for drought tolerance levels of local einkorn wheat genotypes at germination stage and drought related GTFMs can be used not only to reveal genetic variation but also to distinguish the drought tolerant genotypes.

The AIB1 gene polyglutamine repeat length polymorphism contributes to risk of epithelial ovarian cancer risk: a case-control study.

Genes coding for proteins involved in steroid hormone signaling have been identified as ovarian cancer risk-modifier candidates. AIB1 gene (amplified in breast cancer-1), an androgen receptor (AR) coactivator, expresses a polyglutamine (poly-Q) sequence within the carboxyl-terminal coding region. We hypothesized that genotypic variations in the androgen-signaling pathway promote aggressive epithelial ovarian cancer biology and sought to examine the effect of AIB1 poly-Q repeat length on ovarian cancer risk with a case-control study. The genotype analysis of the AIB1 poly-Q repeat was conducted in 3,000 epithelial ovarian cancer (EOC) cases and 3,000 healthy controls. When analyzed as a categorical variable with cutoff of <28 or <29, both of results showed significant asociations. Compared to those with the shorter (<29) AIB1 poly-Q repeat length, women in the category of longer (≥29) poly-Q repeats had a significantly 20% increased EOC risk (odds ratio (OR) = 1.20; 95% confidence interval (CI), 1.08-1.33; P = 5.88 × 10(-4)). When analyzed as a continuous covariate, women with longer average poly-Q repeat length had a significantly increased risk of developing EOC (OR = 1.05 for per poly-Q repeat; 95% CI, 1.00-1.08; P = 0.013). The association was more stronger for per longer allele (OR = 1.07; 95% CI, 1.01-1.12; P = 0.010). These results strongly suggest that there is a significant effect of AIB1 genetic variation on ovarian cancer risk, and AIB1 underlies the development of ovarian cancer.

Polymorphic Repeat Length in the AIB1 Gene and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: A Meta-Analysis of Observational Studies

ObjectivesWe carried out a meta-analysis focusing on the relationship between length of AIB1 gene poly-Q repeat domain as a modifier of breast cancer (BC) susceptibility in patients with BRCA1 and BRCA2 mutation carriers.Data sourcesWe searched MEDLINE and EMBASE for all medical literature published until February, 2012.Study Eligibility criteriaStudies were included in the meta-analysis if they met all the predetermined criteria, such as: (a) case-control or cohort studies; (b) the primary outcome was clearly defined as BC; (c) the exposure of interest measured was AIB1 polyglutamine repeat length genotype; (d) provided relative risk (RR) or odds ratio (OR) estimates and their 95% confidence intervals (CIs).Synthesis methodsTwo of the authors independently evaluated the quality of the studies included and extracted the data. Meta-analyses were performed for case-control and cohort studies separately. Heterogeneity was examined and the publication bias was assessed with a funnel plot for asymmetry.Result7 studies met our predetermined inclusion criteria and were included in the meta-analysis. Overall quality ratings of the studies varied from 0.36 to 0.77, with a median of 0.5. The overall RR estimates of 29/29 poly-Q repeats on risk of BC in BRCA1/2, BRCA1, and BRCA2, were always greater than 1.00; however, this effect was not statistically significant. In the meta-analysis of studies reporting the effect of 28/28 poly-Q repeats on risk of BC in BRCA1/2, BRCA1, and BRCA2, the overall RR decreased below 1.00; however, this effect was not statistically significant. Similar estimates were shown for at least 1 allele of ≤26 repeats.ConclusionsGenotypes of AIB1 polyglutamine polymorphism analyzed do not appear to be associated to a modified risk of BC development in BRCA1 and BRCA2 mutation carriers. Future research on length of poly-Q repeat domain and BC susceptibility should be discouraged and more promising potential sources of penetrance variation among BRCA1 and BRCA2 mutation carriers should be investigated.

AIB1 polymorphisms with breast cancer susceptibility: a pooled analysis of variation in BRCA1/2 mutation carriers and non–carriers

The AIB1 gene (amplified in breast cancer 1), coding for a member of steroid receptor co-activator p160 protein family is involved in regulation of estrogen receptor transactivation influencing the estrogen-dependent gene expression. It contains a glutamine repeat polymorphism and several single nucleotide polymorphisms that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer. Previous studies have shown that these polymorphisms may modify the breast cancer risk in women carrying BRCA1/2 mutations. However, the results remained controversial. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 22 studies were identified, including 3,742 cases and 3,491 controls for AIB1 polyglutamine repeat polymorphism, 2,170 cases and 3,309 controls for Q586H polymorphism, and 2,183 cases and 3,319 controls for T960T polymorphism. Overall, we found no evidence of association for individuals who carried at least one AIB1 allele of 28 or 29 or more repeat with breast cancer risk. But we found increased breast cancer risk in BRCA1/2 mutation carriers for individuals with both alleles ≥29 polyglutamine repeat (OR, 1.64; 95% CI 1.24-2.17). And reduced risk was found to be associated with the Q586H polymorphism among the variant homozygote genotype carriers (OR, 0.42; 95% CI 0.23-0.77). Our results do not support the direct association of AIB1 polyglutamine repeat length and breast cancer. However, we found that BRCA1/2 mutation carriers with both alleles ≥29 repeats have a higher risk of breast cancer.

Role of AIB1 gene in development of esophageal squamous cell carcinoma and its clinicopathologic significance

To investigate the role of AIB1 gene in the development of esophageal squamous cell carcinoma (ESCC) and its clinicopathologic significance. Two tissue microarrays, including 203 cases of ESCC, were prepared. Fluorescence in-situ hybridization (FISH) and immunohistochemistry were performed to detect the amplification of AIB1 gene and expression of its encoded protein in ESCC. The results were correlated with various clinicopathologic parameters. In the 203 cases of ESCC studied, FISH was successful in 115 cases. Amongst those, amplification/gain of AIB1 gene was observed in 15 cases, including high-level amplification in 5 cases (4.3%) and low-level gain in 10 cases (8.7%). As for immunohistochemical study, AIB1 protein was overexpressed in 94 cases of ESCC. There was a significant association of AIB1 overexpression and tumor staging. AIB1 was overexpressed in 66 of the 123 cases in advanced T stages (T3 to 4), compared with 25 of the 80 cases in early T stages (P = 0.008). Those cases with high-level amplification of AIB1 also showed overexpression of its encoded protein. On the other hand, 8 of the 10 cases with low-level gain of AIB1 showed protein overexpression. The remaining 41 of the 100 cases which did not have AIB1 gene amplification/gain demonstrated overexpression of AIB1 protein. Overexpression of AIB1 protein caused by gene amplification/gain or other molecular mechanisms may play an important role in the development and/or progression of a subset of ESCC.

Rapid detection of CAA/CAG repeat polymorphism in the AIB1 gene using DHPLC

Denaturing high-performance liquid chromatography (DHPLC) has been used for rapid and accurate DNA mutation analysis; to extend the DNA fragment lengths analysis. Recently, polymorphism in polyglutamine-coding region of Amplified In Breast cancer gene 1 ( AIB1) was analyzed as an independent genetic risk factor influencing breast cancer onset in carriers of mutation in breast cancer predisposing gene 1 ( BRCA1). We have implemented efficient, cost-effective and rapid method for analysis of the AIB1 polyglutamine repeat polymorphism based on DHPLC analysis (WAVE system) of unlabeled PCR products. This strategy can be useful for genotyping of other trinucleotide repeat polymorphisms using DHPLC in medium/high throughput settings.

AIB1 gene amplification and the instability of polyQ encoding sequence in breast cancer cell lines

BackgroundThe poly Q polymorphism in AIB1 (amplified in breast cancer) gene is usually assessed by fragment length analysis which does not reveal the actual sequence variation. The purpose of this study is to investigate the sequence variation of poly Q encoding region in breast cancer cell lines at single molecule level, and to determine if the sequence variation is related to AIB1 gene amplification.MethodsThe polymorphic poly Q encoding region of AIB1 gene was investigated at the single molecule level by PCR cloning/sequencing. The amplification of AIB1 gene in various breast cancer cell lines were studied by real-time quantitative PCR.ResultsSignificant amplifications (5–23 folds) of AIB1 gene were found in 2 out of 9 (22%) ER positive cell lines (in BT-474 and MCF-7 but not in BT-20, ZR-75-1, T47D, BT483, MDA-MB-361, MDA-MB-468 and MDA-MB-330). The AIB1 gene was not amplified in any of the ER negative cell lines. Different passages of MCF-7 cell lines and their derivatives maintained the feature of AIB1 amplification. When the cells were selected for hormone independence (LCC1) and resistance to 4-hydroxy tamoxifen (4-OH TAM) (LCC2 and R27), ICI 182,780 (LCC9) or 4-OH TAM, KEO and LY 117018 (LY-2), AIB1 copy number decreased but still remained highly amplified. Sequencing analysis of poly Q encoding region of AIB1 gene did not reveal specific patterns that could be correlated with AIB1 gene amplification. However, about 72% of the breast cancer cell lines had at least one under represented (<20%) extra poly Q encoding sequence patterns that were derived from the original allele, presumably due to somatic instability. Although all MCF-7 cells and their variants had the same predominant poly Q encoding sequence pattern of (CAG)3CAA(CAG)9(CAACAG)3(CAACAGCAG)2CAA of the original cell line, a number of altered poly Q encoding sequences were found in the derivatives of MCF-7 cell lines.ConclusionThese data suggest that poly Q encoding region of AIB1 gene is somatic unstable in breast cancer cell lines. The instability and the sequence characteristics, however, do not appear to be associated with the level of the gene amplification.

SRC-3/AIB1 protein and gene amplification levels in human esophageal squamous cell carcinomas

It has been suggested that the steroid receptor coactivatior-3 (SRC-3) gene, also known as AIB1, ACTR, RAC3, p/CIP and TRAM-1, located at 20q12, plays an oncogenic role in several types of human cancers. In this study, we examined the encoded protein expression of SRC-3 and its copy number in 221 human esophageal squamous cell carcinomas (ESCCs). In this ESCC series, the overexpression and increased copy number of SRC-3 gene was detected in 46 and 13% of ESCCs, respectively. In addition, overexpression of SRC-3 was observed more frequently in primary ESCCs in late T stages (T3/T4) than that in earlier T1/T2 stages (P<0.05), but no significant association of expression of SRC-3 and status of lymph node metastases was observed (P>0.05). These results suggest that overexpression of SRC-3, caused by gene amplification/gain or other molecular mechanisms, might provide a selective advantage for the development and local invasion of certain subsets of ESCC. In addition, a significant correlation (P<0.05) of overexpression of SRC-3 with increased cell proliferation (through detection of Ki-67 expression) was observed in these ESCCs. These findings suggest a potential role of SRC-3 in the control of ESCC cell proliferation; such may be responsible, at least in part, for tumorigenesis and/or progression of ESCC.

The AIB1 Polyglutamine Repeat Does Not Modify Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and amplification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large sample size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Overexpression of an N-Terminally Truncated Isoform of the Nuclear Receptor Coactivator Amplified in Breast Cancer 1 Leads to Altered Proliferation of Mammary Epithelial Cells in Transgenic Mice

Amplified in breast cancer 1 (AIB1, also known as ACTR, SRC-3, RAC-3, TRAM-1, p/CIP) is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of genes activated through steroid receptors, such as estrogen receptor alpha (ER(alpha)). The AIB1 gene and a more active N-terminally deleted isoform (AIB1-Delta3) are overexpressed in breast cancer. To determine the role of AIB1-Delta3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven over-expression of human AIB1/ACTR-Delta3 (CMVAIB1/ACTR-Delta3 mice). AIB1/ACTR-Delta3 transgene mRNA expression was confirmed in CMV-AIB1/ACTR-Delta3 mammary glands by in situ hybridization. These mice demonstrated significantly increased mammary epithelial cell proliferation (P < 0.003), cyclin D1 expression (P = 0.002), IGF-I receptor protein expression (P = 0.026), mammary gland mass (P < 0.05), and altered expression of CCAAT/enhancer binding protein isoforms (P = 0.029). At 13 months of age, mammary ductal ectasia was found in CMV-AIB1/ACTR-Delta3 mice, but secondary and tertiary branching patterns were normal. There were no changes in the expression patterns of either ER(alpha) or Stat5a, a downstream mediator of prolactin signaling. Serum IGF-I levels were not altered in the transgenic mice. These data indicate that overexpression of the AIB1/ACTR-Delta3 isoform resulted in altered mammary epithelial cell growth. The observed changes in cell proliferation and gene expression are consistent with alterations in growth factor signaling that are thought to contribute to either initiation or progression of breast cancer. These results are consistent with the hypothesis that the N-terminally deleted isoform of AIB1 can play a role in breast cancer development and/or progression.

Somatic instability of the DNA sequences encoding the polymorphic polyglutamine tract of the AIB1 gene

Background:AIB1 contains a polymorphic polyglutamine tract (poly Q) that is encoded by a trinucleotide CAG repeat. Previously there have been conflicting results regarding the effect of the poly Q tract...

Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers.

Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other factors may modify cancer risk from specific mutations. One possible mechanism is an epigenetic effect of polymorphisms in other genes. Genes involved in hormonal signal transduction are possible candidates. The AIB1 gene, an estrogen receptor (ER) coactivator, is frequently amplified in breast and ovarian tumors. Variation of a CAG repeat length has been reported within this gene that encodes a polyglutamine repeat in the C-terminus of the protein. Three hundred eleven BRCA1/2 mutation carriers (257 were of Ashkenazi origin) were genotyped for the AIB1 polyglutamine repeat. Relative risks (RR) were estimated using a maximum likelihood approach. The estimated breast cancer (BC) RR per average repeat length adjusted for population type (Ashkenazi vs. non-Ashkenazi) was 1.15 (95% CI = 1.02-1.30; p = 0.01) for BRCA1/2 carriers, and 1.25 (95% CI = 1.09-1.42; p = 0.001) when analysis was restricted to BRCA1 carriers. RR of BC was 1.17 (95% CI = 0.91-1.74), for individuals with 2 alleles >/=29 polyglutamine repeats and 0.78 (95% CI = 0.50-1.16) for those with at least 1 allele of </=26 repeats, compared to individuals with the common genotypes 28;28, 28;29 or 28;30. The corresponding BC RR in BRCA1 mutation carriers was 0.55 (95% CI = 0.34-0.90) and 1.29 (95% CI = 0.85-1.96) in those with </=26 and >/=29 repeats respectively (p = 0.025). These results indicate significant association of the risk for BC in carriers of BRCA1 mutations with the polyglutamine chain of the AIB1 gene. Longer repeat length correlates with elevated risk, whereas in carriers of a shorter AIB1 allele BC risk was reduced. The AIB1 polyglutamine length did not affect BC risk among BRCA2 mutation carriers.