gms | German Medical Science

Loss of heterozygosity (LOH) of markers on human chromosome 8 is frequently found in a variety of human neoplasias including breast carcinomas indicating the presence of one or more tumor suppressor genes (TSG). By deletion mapping using microsatellite markers covering the whole human chromosome 8 a homozygous deletion in a breast tumor of one patient was observed. Following a positional cloning strategy we have identified the gene ST18 (for suppression of tumorigenicity 18, breast carcinoma, zinc finger protein), within a region of chromosome 8q11 around the marker D8S1110. The gene encodes a zinc finger DNA binding protein with 6 fingers of the C2HC type. The gene product is located in the cell nucleus as shown by GFP-ST18 fusion proteins as well as antibodies against a synthetic peptide. 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 tumor cells we detected aberrantly spliced ST18 transcripts. In breast cancer cell lines and the majority of primary breast tumors ST18 mRNA is significantly downregulated. The strong correlation between ST18 promoter hypermethylation and loss of ST18 expression in the tumor cells suggests that this epigenetic mechanism is responsible for tumor specific downregulation of ST18 expression. In addition, luciferase assays with deletion mutants of the promoter region revealed regions that show much higher luciferase activity in normal cells in comparison to tumorigenic cells. 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. Our results suggest that ST18 is a breast cancer tumor suppressor gene located on chromosome 8q11. The study was supported by the Deutsche Forschungsgemeinschaft Sche373/4-1