Epigenetics and Breast Cancer

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 36
  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
(No Transcript)
10
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.

11
Suspect Environmental Exposures

• Cosmetologists and hairdressers
• Printers and dye workers
• Health care workers
• Metal plate workers

12
Hormones, Growth Factors and Epigenetics

• Epigenetic drugs can restore the expression of
  estrogen, progesterone, androgen and retinoic
  acid receptors.

13
(No Transcript)