ST18 is a breast cancer tumor suppressor gene at human chromosome 8q11.2

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany
Oncogene (Impact Factor: 8.46). 01/2005; 23(57):9295-302. DOI: 10.1038/sj.onc.1208131
Source: PubMed


We have identified a gene, ST18 (suppression of tumorigenicity 18, breast carcinoma, zinc-finger protein), within a frequent imbalanced region of chromosome 8q11 as a breast cancer tumor suppressor gene. The ST18 gene encodes a zinc-finger DNA-binding protein with six fingers of the C2HC type (configuration Cys-X5-Cys-X12-His-X4-Cys) and an SMC domain. ST18 has the potential to act as transcriptional regulator. ST18 is expressed in a number of normal tissues including mammary epithelial cells although the level of expression is quite low. In breast cancer cell lines and the majority of primary breast tumors, ST18 mRNA is significantly downregulated. A 160 bp region within the promoter of the ST18 gene is hypermethylated in about 80% of the breast cancer samples and in the majority of breast cancer cell lines. The strong correlation between ST18 promoter hypermethylation and loss of ST18 expression in tumor cells suggests that this epigenetic mechanism is responsible for tumor-specific downregulation. We further show that ectopic ST18 expression in MCF-7 breast cancer cells strongly inhibits colony formation in soft agar and the formation of tumors in a xenograft mouse model.

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Available from: André Rosenthal, Aug 29, 2014
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    • "In accordance, a number of the breast-specific methylated transcription factors identified in this work were previously linked to breast differentiation and carcinogenesis. Thus, loss of ALX4 caused defective mouse mammary epithelial morphogenesis and ALX4 expression was reduced in breast cancers [22], GATA5 was associated with hPR-B expression in mammary cells and might contribute to breast cancer risk [23], MGMT methylation differed between DCIS and invasive breast cancers [24], SOX10 expression was linked to differentiation and transformation of myoepithelial/basal breast cells [25], ST18 is a tumor suppressor that was hypermethylated and silenced in breast cancers [26] and TP73 down-regulation led to epithelial to mesenchymal transition and marked proliferation and migration of mammary epithelial cells [27]. Of special interest, for TRIM29 it was previously reported that it could either function as a tumor suppressor in luminal ER positive breast cells [12] or as an oncogene in pancreatic, lung and various other cancers [8], [16] [7]. "
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    ABSTRACT: Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer.
    PLoS ONE 03/2014; 9(3):e91805. DOI:10.1371/journal.pone.0091805 · 3.23 Impact Factor
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    • "Staining intensity and pattern were scored by three independent observers blinded to the patient diagnosis (Figure 3). ST18 was found to be expressed mostly within the nucleus as previously reported (Jandrig et al., 2004), reflecting its function as a transcription factor (Yang et al., 2008). ST18 was found to be strongly overexpressed in the non-lesional epidermis of PV patients as compared with controls (P-value ¼ 0.00026). "
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    ABSTRACT: Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by anti-epithelial antibodies, leading to disruption of cell-cell adhesion. Although the disease is exceedingly rare worldwide, it is known to be relatively prevalent in Jewish populations. The low prevalence of the disease represents a significant obstacle to a genome-wide approach to the mapping of susceptibility genes. We reasoned that the study of a genetically homogeneous cohort characterized by a high prevalence of PV may help exposing associated signals while reducing spurious results due to population sub-structure. We performed a genome-wide association study using 300K single-nucleotide polymorphisms (SNPs) in a case-control study of 100 PV patients of Jewish descent and 397 matched control individuals, followed by replication of significantly associated SNPs in three additional cohorts of Jewish, Egyptian, and German origin. In addition to the major histocompatibility complex locus, a genomic segment on 8q11.23 that spans the ST18 gene was also found to be significantly associated with PV. This association was confirmed in the Jewish and Egyptian replication sets but not in the German sample, suggesting that ST18-associated variants may predispose to PV in a population-specific manner. ST18 regulates apoptosis and inflammation, two processes of direct relevance to the pathogenesis of PV. Further supporting the relevance of ST18 to PV, we found this gene to be overexpressed in the skin of PV patients as compared with healthy individuals.
    Journal of Investigative Dermatology 03/2012; 132(7):1798-805. DOI:10.1038/jid.2012.46 · 7.22 Impact Factor
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    • "This is not novel since insulin expression was previously observed in brain, thymus, liver and bone marrow [21]. ST18 mRNA proved one of the most beta cell-selective transcripts but was also qPCR-detected in brain, and was previously observed in the human breast ductal cells [22]. These low expression-signals could reflect illegitimate (ectopic) expression of cell type-selective genes [23]. "
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    ABSTRACT: The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators. A panel of 332 conserved beta cell biomarker genes was found to discriminate both isolated and laser capture microdissected beta cells from all other examined cell types. Of all conserved beta cell-markers, 15% were strongly beta cell-selective and functionally associated to hormone processing, 15% were shared with neuronal cells and associated to regulated synaptic vesicle transport and 30% with immune plus gut mucosal tissues reflecting active protein synthesis. Fasting specifically down-regulated the latter cluster, but preserved the neuronal and strongly beta cell-selective traits, indicating preserved differentiated state. Analysis of consensus binding site enrichment indicated major roles of CREB/ATF and various nutrient- or redox-regulated transcription factors in maintenance of differentiated beta cell phenotype. Conserved beta cell marker genes contain major gene clusters defined by their beta cell selectivity or by their additional abundance in either neural cells or in immune plus gut mucosal cells. This panel can be used as a template to identify changes in the differentiated state of beta cells.
    PLoS ONE 09/2011; 6(9):e24134. DOI:10.1371/journal.pone.0024134 · 3.23 Impact Factor
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