115761

ARL11

ARLTS1;ADP-ribosylation factor-like 11;ARL11;ADP-ribosylation factor-like 11

ADP-ribosylation factor-like protein 11|ADP-ribosylation factor-like tumor suppressor protein 1

13q14.2

protein-coding

Count: 2; Pubmed_search,Generif

Genetic factors that contribute to the risk of breast cancer are largely not known and association studies have revealed several genes with low penetrance risk alleles for breast cancer. Analysis of these genes may provide important information on the risk factors affecting carcinogenesis. Variations in the ARLTS1, RAD51 and MDM2 genes have been associated with increased risk of different cancer types but for breast cancer the results are not consistent. In this study we investigated the role of the allelic variants in candidate genes acting in the tumor suppressor, DNA repair and p53 pathways as risk factors for familial breast cancer in 147 patients displaying characteristics of familial disease. Presence of the polymorphic variants were investigated by amplification of the corresponding regions and restriction fragment length polymorphism analysis. Genotype and allele frequencies in the patients were significantly different for all three variants. Our results indicate that the polymorphic variants might affect individual susceptibility towards breast cancer.

ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) is a member of the ARF family of the Ras superfamily of small GTPases that are known to be involved in multiple regulatory pathways altered in human carcinogenesis. Here, we review recent work that has provided insights into the role of this small gene as an emerging player in both familial and sporadic cancers of several histotypes. ARLTS1 is a low penetrance gene that is primarily dysregulated in sporadic lung cancer by promoter hypermethylation. Two ARLTS1 polymorphisms are also associated with familial cancer risk. Down-regulation of ARLTS1 is seen in all lung cancer cell lines studied and in a significant proportion (37%) of primary lung tumors. Restoration of ARLTS1 expression in ARLTS1-deficient lung cancer cell lines by either demethylation or adenoviral transduction leads to apoptosis via caspase-dependent mechanisms. Furthermore, ARLTS1 re-expression induces an in vivo decreased tumor growth in preclinical models of lung cancer. Microarray analysis of gene expression patterns in cells transduced with ARLTS1 demonstrates that various pathways involved in cell survival, proliferation and development mediate its pro-apoptotic effects.

ARLTS1 is a newly characterized tumor suppressor gene located at chromosome 13q14.3 and involved in the pathogenesis of various types of tumors: two single-nucleotide polymorphisms, one of them responsible for protein truncation, were found statistically associated with familial malignancies, whereas DNA hypermethylation and genomic deletions have been identified as a mechanism of ARLTS1 down-regulation in sporadic cancers. We found that in a large portion of lung carcinomas (37%) and in all analyzed lung cancer cell lines, ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After its restoration by adenoviral transduction, ARLTS1-negative A549 and H1299 cells underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the ability of A549 and H1299 to form tumors in nude mice. Finally, we identified approximately 650 transcripts differentially expressed after restoration of ARLTS1 expression in A549 cells, suggesting that various pathways involved in cell survival, proliferation, signaling, and development mediate the effects of wild-type ARLTS1 in a lung cancer system.