Abstract 800: Dysregulation of DLL4 gene expression in Li-Fraumeni syndrome and tumorigenesis

Abstract Li-Fraumeni Syndrome (LFS), a clinically and genetically rare heterogeneous cancer syndrome, is characterized primarily by a p53 (TP53) gene mutation. This study is an attempt to understand why 30-40% of LFS patients who do not harbor p53 mutation are nonetheless besieged by the same preponderance of primary cancers, die at an early age, and at the same rate as those with the p53 mutation. LFS provides powerful insights into our understanding of the somatic mutations present in sporadic cancers influenced by p53. The p53 protein is a transcription factor that guards against genomic instability by inducing target genes that mediate its functions. Utilizing cytogenetic techniques, we previously discovered a novel balanced reciprocal translocation t(11;15)(q23;q15) between chromosomes 11 and 15 in the normal skin fibroblasts of a patient with LFS who had bilateral breast cancer but was homozygous for wild-type p53. Analysis of the breakpoint regions of this translocation yielded a number of genes; of particular interest was DLL4 (Delta-like ligand 4, locus 15q15.1), which encodes a ligand that binds to Notch receptors. Notch signaling controls cell fate specification during embryonic and postnatal development. DLL4 is a putative regulator of T cell lineage and thymopoiesis. In this study, we analyzed DLL4 gene expression and regulation in tumorigenesis. We also analyzed the transcriptional regulation of the DLL4 promoter. Our data reveal that DLL4 expression is abrogated in the normal skin fibroblasts of all LFS patients under study and markedly down-regulated in breast cancer cells and neuroblastoma cells due to TP53 mutation, DNA methylation or gene disruption caused by a balanced reciprocal translocation between chromosomes 11q23 and 15q15. Immunohistochemistry (IHC) staining corroborated the down-regulation of DLL4 in cancer tissue samples from different organs. These findings taken together not only have possible implications for karyotype-phenotype correlation in carcinogenesis, specifically of breast cancer, but also shed light on the possible implication of DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in normal skin fibroblasts of LFS patients as well as breast and brain cancer cells is significant and supports the concept that this ligand may play a role in cancer immune-surveillance and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth. This demonstrates that DLL4 may provide a strong platform as an immuno-therapeutic target in LFS and breast cancer patients. Citation Format: Zhixing Yao, Zaki A. Sherif. Dysregulation of DLL4 gene expression in Li-Fraumeni syndrome and tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 800. doi:10.1158/1538-7445.AM2015-800