Amplification of the BCAS2 gene at chromosome 1p13.3-21 in human primary breast cancer.
ABSTRACT BCAS2 is a novel gene isolated from breast cancer cell line by differential display technique. Previously we reported that BCAS2 gene is localized on chromosome 1p13.3-21 and is up-regulated by gene amplification in breast cancer cell lines MCF-7 and BT-20. In this study, we investigated the amplification of the BCAS2 gene in a series of 104 gynecological primary tumors by means of Southern blot analysis. The BCAS2 gene was amplified in two of 60 primary breast cancer tissues, whereas no amplification was detected in any of endometrial (0/26) and cervical (0/18) tumor tissues. Gene amplification was also not detected in a series of pancreatic (0/9) and gastric (0/6) cancer cell lines. An enhanced green fluorescent protein assay revealed that BCAS2 protein seems to be translocated into the nucleus. Although frequent deletions of the proximal region of chromosome 1p13.3-21 have been found in primary breast cancer, our results support first evidence of amplification within this region and indicate that BCAS2 gene codes for a nuclear protein.
- SourceAvailable from: Akihiko Konagaya[Show abstract] [Hide abstract]
ABSTRACT: Heregulin beta-1 (HRG) is an extracellular ligand that activates mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI3K)/Akt signaling pathways through ErbB receptors. MAPK and Akt have been shown to phosphorylate the estrogen receptor (ER) at Ser-118 and Ser-167, respectively, thereby mimicking the effects of estrogenic activity such as estrogen responsive element (ERE)-dependent transcription. In the current study, integrative analysis was performed using two tiling array platforms, comprising histone H3 lysine 9 (H3K9) acetylation and RNA mapping, together with array comparative genomic hybridization (CGH) analysis in an effort to identify HRG-regulated genes in ER-positive MCF-7 breast cancer cells. Through application of various threshold settings, 333 (326 up-regulated and 7 down-regulated) HRG-regulated genes were detected. Prediction of upstream transcription factors (TFs) and pathway analysis indicated that 21% of HRG-induced gene regulation may be controlled by the MAPK cascade, while only 0.6% of the gene expression is controlled by ERE. A comparison with previously reported estrogen (E2)-regulated gene expression data revealed that only 12 common genes were identified between the 333 HRG-regulated (3.6%) and 239 E2-regulated (5.0%) gene groups. However, with respect to enriched upstream TFs, 4 common TFs were identified in the 14 HRG-regulated (28.6%) and 13 E2-regulated (30.8%) gene groups. These results indicated that while E2 and HRG may induce common TFs, the regulatory mechanisms that govern HRG- and E2-induced gene expression differ.PLoS ONE 02/2008; 3(3):e1803. · 3.53 Impact Factor
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ABSTRACT: Background: The overexpression of oestrogen-related receptor-β (ERRβ) in breast cancer patients is correlated with improved prognosis and longer relapse-free survival, and the level of ERRβ mRNA is inversely correlated with the S-phase fraction of cells from breast cancer patients. Methods: Chromatin immunoprecipitation (ChIP) cloning of ERRβ transcriptional targets and gel supershift assays identified Breast Cancer Amplified Sequence 2 and Follistatin as two important downstream genes that help to regulate tumourigenesis. Confocal microscopy, co-immunoprecipitation (CoIP), western blotting and quantitative real-time PCR confirmed the involvement of ERRβ in oestrogen signalling. Results: Overexpressed ERRβ induced Follistatin-mediated apoptosis in breast cancer cells, and E-cadherin expression was also enhanced through upregulation of Follistatin. However, this anti-proliferative signalling function was challenged by ERRβ-mediated BCAS2 up-regulation, which inhibited Follistatin transcription through the down-regulation of β-catenin/TCF4 recruitment to the Follistatin promoter. Interestingly, ERRβ-mediated up-regulation of BCAS2 down-regulated the major G1-S transition marker Cyclin D1, despite the predictable oncogenic properties of BCAS2. Interpretation: Our study provides the first evidence that ERRβ, which is a coregulator of ER also acts as a potential tumour suppressor molecule in breast cancer. Our current report also provides novel insights into the entire cascade of ERRβ signalling events, which may lead to BCAS2-mediated blockage of the G1/S transition and inhibition of the epithelial to mesenchymal transition through Follistatin-mediated regulation of E-cadherin. Importantly, MMP7, which is a classical mediator of metastasis and E-cadherin cleavage, was also restricted as a result of ERRβ-mediated Follistatin overexpression.British Journal of Cancer 01/2014; · 5.08 Impact Factor
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ABSTRACT: The putative CCDC106 protein was previously identified as a p53-interacting partner by automated yeast two-hybrid screening, but its sequence and function have not been validated experimentally. Here, we identified three variant transcripts of the CCDC106 gene; these transcripts differ in their second exons due to the use of different splice acceptor site, but encode an identical protein of 280 residues. A bipartite nuclear localisation signal at residues 151-164 mediates the nuclear localisation of CCDC106. Double immunofluorescence staining revealed the colocalisation of endogenous CCDC106 and p53 protein in nuclei. The in vivo interaction between CCDC106 and p53 was confirmed by a co-immunoprecipitation assay. Furthermore, we demonstrated that CCDC106 promotes the degradation of p53 protein and inhibits its transactivity.FEBS letters 02/2010; 584(6):1085-90. · 3.54 Impact Factor