Histone Methylation as a Marker of Breast Cancer Progression
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The fundamental molecular mechanisms that contribute to sporadic breast cancer progression remain unknown. Discrete genetic factors that predispose an individual to the disease appear to be lacking, indicating that mechanisms other than DNA mutation must be involved. Increasing evidence demonstrates that the disruption of epigenetic mechanisms (i.e., changes in gene expression without changes in the DNA) contribute to cellular transformation and cancer progression, including breast cancer. We recently reported that methylation of histone H4 lysine 20 (H4 Lys20) is an epigenetic event that is critical for the formation of heterochromatin, or transcriptionally silent (inactive) regions of the genome. We have also found that global changes in H4 Lys20 methylation levels are associated with aging, differentiation defects and genomic instability; all of which are hallmarks of aggressive cancers.
 
 
 
 
 
 
 
 Based on our findings, we hypothesize that aberrant genome-wide alterations in heterochromatin, as measured by H4 Lys20 methylation, plays a direct role in sporadic breast cancer progression. We further hypothesize that the regions where changes are detected may likely serve as future epigenetic markers for the enhanced detection, prognosis and, perhaps, treatment of sporadic breast cancer. Our aims are to: (1) determine and compare the genomic patterns of H4 Lys20 methylation of normal breast cells and breast cancer cells using an innovative “ChIP” technique (chromatin immunoprecipitation assay), (2) analyze the data to identify regions with consistent significant changes in H4 Lys20 methylation (heterochromatin "markers") during progression, and (3) verify each "marker" using standard ChIPs, RT-PCR and chromatin accessibility assays. Established normal breast and cancer cell lines (non-metastatic and metastatic) will be used for comparison purposes. The genomic regions containing H4 Lys20 methylation will be isolated from each cell line using a novel panel of H4 Lys20 methyl-specific antibodies that we have developed. The resulting H4 Lys20 methyl-enriched DNA will be used as hybridization probes on a unique DNA microarray chip containing 6800 annotated human CpG islands. Analysis of the different groups will lead to information on the normal state of heterochromatin in breast epithelial tissue and how these patterns change during sporadic breast cancer progression (i.e., potential markers).
 
 
 
 
 
 
 
 The potential impact of this research on breast cancer and breast cancer patients will be relatively immediate. The identification and verification of novel epigenetic markers will quickly translate into high-throughput screening of these regions from patients to aid physicians in the detection, assessment and treatment of the disease. In addition, these experiments will enhance the current understanding of the molecular mechanisms that underlie normal breast cell physiology and the pathways that lead to malignant transformation.