Abstract
The Li-Fraumeni Syndrome (LFS), a genetically rare heterogeneous cancer syndrome, is characterized primarily by a germline p53 (TP53) gene mutation. We recently discovered a balanced reciprocal chromosomal translocation t(11;15)(q23;q15) in the non-cancerous skin fibroblasts of a bilateral breast cancer patient in LFS family. This prompted us to investigate the breakpoint region of the translocation, which uncovered a gene that encodes a Notch ligand, DLL4, (locus at 15q15.1), a key target in tumor vasculature. We analyzed DLL4 gene expression and protein level in LFS non-cancerous skin fibroblast cell lines and non-LFS cancer cell lines. DLL4 is abrogated in all the LFS cells and drastically down-regulated in breast (MCF7) and brain (IMR32) cancer cells and tumor tissue samples. However, DNA methylation studies revealed that DLL4 promoter is silenced only in MCF7 but not in LFS cells. We further investigated the regulation of DLL4 gene expression by ChIP assays, which demonstrated that p53 binds to DLL4 promoter through its association with CTCF, a chromosomal networking protein CCCTC binding factor. This implies a possible karyotype-phenotype correlation with respect to DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in LFS as well as breast and brain cancer cells is significant and supports the concept that this ligand may also play a role in cancer immune-surveillance; and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth. Therefore, DLL4 may provide a strong platform as an immuno-therapeutic target in LFS and cancer patients.
Highlights
The Li-Fraumeni syndrome (LFS; OMIM #151623) is a clinically and genetically heterogeneous cancer syndrome with inherited germline heterozygous mutation in the tumor suppressor gene, p53 (TP53), which can provide powerful insights into our understanding of the somatic mutations present in sporadic cancers
The results show that the expression of most of these genes and especially delta- like ligand-4 (DLL4), is dysregulated in LFS cell lines as well as in breast cancer cell line (MCF7) and neuroblastoma cell line (IMR32) when compared to normal foreskin human fibroblast cell line, HS27
The results confirmed that the expression of Delta-like ligand 4 (DLL4) is abrogated in normal skin fibroblasts (NSFs) of LFS family regardless of their status as wild-type (WT) TP53 carriers or mutation (MT) carriers
Summary
The Li-Fraumeni syndrome (LFS; OMIM #151623) is a clinically and genetically heterogeneous cancer syndrome with inherited germline heterozygous mutation in the tumor suppressor gene, p53 (TP53), which can provide powerful insights into our understanding of the somatic mutations present in sporadic cancers. The Notch signaling pathway is instrumental in mammalian development, cell fate determination, differentiation, proliferation, angiogenesis and survival in eukaryotes [5,6,7,8,9]. It plays an important role in tumor suppression through inhibition of proliferation, differentiation and apoptosis in multiple cell types [1012]. DLL4 can be expressed in brain, retina, thymus and hematopoietic cells, it is primarily expressed in endothelial cells of developing vessels and sprouting blood vessels [14]
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