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Epigenetics and Breast cancer- Evening Session -

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Christian Scerri

on 5 February 2017

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Transcript of Epigenetics and Breast cancer- Evening Session -

Epigenetics
and Breast Cancer

From the Greek word “epigenesis” - the influence of genetic processes on development
Many cancers are a result of inactivation of a tumour suppressor genes

Suppressor genes can be inactivated by DNA methylation.

Two basic models for how tumour suppressor genes can be methylated:
the stochastic model and
the instructive model
Epigenetics and Cancer
Environmental issues
Can cause epigenetic changes

Results might be seen decades after exposure

Epigenetics changes could be inherited by children

Examples include smoking, dietary factors as obesity, hyperglycemia, inflammation, hypoxia and oxidative stress

Interestingly, social factors e.g. stress, parental neglect, can also play a role.
Genetics
Genetics brought order within the field of biology.

Every physical aspect of a person was summarized and guided by a simple code embedded in every cell of the body.
The Genetic Dogma
But was that all?
Clearly not as otherwise we should not have this:
Enter Epigenetics
Environmental and lifestyle factors can twist, adjust, and move the DNA to express it in different ways even through the same genes
Epigenetic changes can switch genes on or off and determine which proteins are translated.
DNA damage repaired?
Is all DNA replicated?
Is the environment favourable?
Are all chromosomes attached to the spindle?
Continue dividing or stop and differentiate?
Genes Involved in Tumour Transformation
3 types of Genes
2. Oncogenes
3. DNA Repair Genes
1. Tumour Suppressor Gene
Folate
A natural occuring derivative of Folic Acid

Folic acid requires transformation in the body - not always possible.

Lack of folate, reduces total DNA methylation but can result in a paradoxical methylation of specific genes.
Genes are switched off when methylated and switched on when demethylated.
spinach, asparagus, broccoli, cauliflower, corn, carrots, celery, beans, peas, lentils, squash, citrus fruit, grapes, banana, avocado, seeds, nuts
Methionine
An essential amino acid
Major effects of these three agents:

Results in demethylation -
switching on
genes

1 alcohol drink per day increase risk by about 7%

Moderation is the key word - one drink a day has health benefits e.g lowers risk of heart disease and hypertension

> 1 drink a day - no benefits

Diagnosis, prognosis and
prediction of treatment outcome
Currently no ideal screening test for young (20-40) women at moderate risk of breast cancer/

Identifying a biomarker for the early detection of breast cancer would be ideal

Study published in 2010 had identified over 700 genes that were either upregulated or downregulated in breast cancer.
Sensitivity (actual positives correctly identified ) = 80.6%
Specificity (negatives correctly identified) = 78.3%.

Mammography - Sensitivity 83 - 95% (lower in younger women, and very low <35 years)
Specificity - >80%
So why not implement it?
Mostly lack of expertise, cost and sensitive material (RNA)
Methylation patterns in cell free DNA

The methylation status of a number genes has already been shown to be able to identify early breast cancer.

One shall be able to identify the presence, type and most probably even spread of breast cancer through a blood test

With this information one can then identify the best way towards and which treatment to give.
The future?
DNA methyltransferase
S-adenosylmethionine
Methylation of Tumour Suppressor Gene (TSG) occurs by chance (environmental)

Presence of oncoprotein and suppressed TSG, favours growth of tumour cells.
Oncoprotein targets methylation of TSG

Environment plays a minor role in methylation but would play a major role in oncogene activation
Sources of Folate
Ethyl Alcohol
or better known as alcoholic drinks
Antagonist to methylation agents e.g folate
Induces global hypomethylation including genes involved in initiation of cell invasion and metastasis

Paradoxical hypermethylation of specific genes in particular genes involved in:
DNA repair
Cellular homeostasis
Reduction of cell invasion
Cell cycle regulation
Apoptosis
Once cancer has occurred, they can also help in the methylation of estrogen receptor (ER) genes that transform the cancer from ER +ve (better prognosis and responds to anti-hormonal therapy) to ER -ve)
Other important epigenetic changes:
One survival ploy in cancer tissue is Angiogenesis

Switching off angiogenetic genes - reduces cancer risk. Beta-carotene
(= carrots) has this effects as it helps methylate these genes
All tissues require oxygenation but cancer tissue requires more!
Biomarkers for tailored treatment and response
BMRS1 - correlated with poor prognosis

serum RASSF1A DNA methylation shows good response to tamoxifen treatment and favourable prognosis

Patients with methylated PITX2 are less likely to develop distant metastasis - a possibility to spare them adjuvant chemotherapy.
DNA methylation modification as therapeutic target
DNMT inhibitor and demethylating agents e.g. zebularine - inhibits methylation and activates cell stabilising genes (arrests cells in the S-phase)
Old drugs with new applications:
Procaine (local anesthetic) and procainamide, (antiarrhythmic drug), - demethylating activity in cancer cells, leading to the reexpression of silenced tumor-suppressor genes.
EGCG, the main polyphenol compound in
green tea
- increases tumour suppressor gene activity.
Cell Cycle
The distant past was the era of curses and witches,
The present is the era of genetics
The near future shall be the era of epigenetics
Both based on Shakespeare
Yet
Totally different films
1936
1996
Obesity and High Fat Diet
In postmenopausal women, adipose tissue is the main tissue producing estrogens.

Estrogens induce the growth of breast cancer.

High level of fat cells (obesity) increases a substance called Leptin.

Leptin stimulates tumour growth

Obesity has been shown to upregulate inflammatory substances that induces growth and angiogenesis

Apart from inducing chronic inflammation, the pro-inflammatory chemicals, switch on of various genes involved in growth and invasiveness of (breast) cancer
Obesity and High Fat Diet
Full transcript