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Epigenetics and Breast Cancer

Epigenetics and Breast Cancer. Dr. Diego Montoya-Durango University of Louisville School of Medicine and Center for Genetics and Molecular Medicine. What is Epigenetics?. Heritable changes in phenotype or gene expression caused by mechanisms other than changes in DNA sequence.

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Epigenetics and Breast Cancer

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  1. Epigenetics and Breast Cancer Dr. Diego Montoya-Durango University of Louisville School of Medicine and Center for Genetics and Molecular Medicine

  2. What is Epigenetics? Heritable changes in phenotype or gene expression caused by mechanisms other than changes in DNA sequence. Epigenetics causes the organism's genes to behave differently, such as the changes seen when cells differentiate or become malignant.

  3. Breast Cancer • Pathology • Grade of tumor • Protein & gene expression • Stage of a tumor • Squamous Cell Carcinoma • Ductal Carcinoma

  4. Epigenetic Biology of Normal Cells • The methylation of cytosines in DNA is the most widely studied epigenetic modification with 3–6% of all cytosines methylated in normal human DNA. The methylation of DNA is located in regions known as CpG islands. • Repetitive genomic sequences are highly methylated to protect chromosomal integrity by preventing the reactivation of transposable elements such as LINES, SINES, HERVS. • The healthy cell regulates genes and tissue-specific genes in the germ line through DNA methylation, such as genomic imprinting and X-chromosome inactivation.

  5. Epigenetic Biology of Normal Cells • Lysine methylation at H3K9, H3K27, and H4K20 gene silencing • Lysine methylation at H3K4, H3K36, and H3K79 gene activation.

  6. Functional Interactions between DNA and Histones

  7. Epigenetic Biology of Cancer Cells: DNA • The coexistence of gene-specific promoter hypermethylation and global genomic DNA hypomethylation is an epigenetic characteristic of cancer cells. • Genes regulated via methylation mechanisms include tumor suppressors, cell cycle regulators, DNA repair enzymes and regulators of apoptosis, among others. • Global genomic DNA hypomethylation is a feature of malignancy because there is a loss in the methylation of repetitive sequences of the genome. This has been linked to the chromosomal instability of cancer cells

  8. Epigenetic Biology of Cancer Cells: Histones • Loss of the monoacetylated Lys16 and trimethylated Lys20 residues of histone H4 appears in the early phase of cell transformation and increases with tumor progression. • Histone modifications may or may not be associated with promoter hypermethylation. • The tumor suppressor gene CDKN2/p16 is silenced via aberrant methylation in breast cancer (33%), prostate cancer (60%), renal cancer (23%), and colon cancer (92%).

  9. Breast Cancer and the Environment • The “established genetic risk factors” can only explain ~25% of the breast cancer risk in human populations. • Chemicals at the workplace and home, diet, pesticides, endocrine disruptors, and lifestyle have been implicated as important risk factors in breast cancer. • Some environmental chemicals cross the placenta and target the offspring, while others appear in human breast milk.

  10. Suspect Environmental Exposures • Cosmetologists and hairdressers • Printers and dye workers • Health care workers • Metal plate workers

  11. Hormones, Growth Factors and Epigenetics Epigenetic drugs can restore the expression of estrogen, progesterone, androgen and retinoic acid receptors.

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