| ANTI-AGEING MEDICINE | PEER-REVIEW
Genotypes and risk of breast cancer Gene/Allele
CYP1A1*2A* CYP1B1*3*
CYP17A1
(T34C)* GSTM1*
GSTT1* SULT1A1*2* COMT (V158M)*
ER (Xbal)* ER (Pvull)*
Sources of oestrogen exposure Evidence is being accumulated to make it clear that oestrogen exposure from both exogenous and endogenous sources is an important factor in developing hormone-sensitive cancers. Environmental oestrogens can induce, overload and potentially modify some of the SNPs involved in oestrogen detoxification. This can possibly lead to the production of more harmful oestrogen metabolites and also have the ability to mimic harmful oestrogens in the body22, 23
. These
environmental oestrogens are responsible for breast cancer being labelled an environmental disease. These are phthalates from cosmetics, polychlorinated biphenyls, dioxins, polycyclic aromatic hydrocarbons, perchloroethylene, and phenols, but also oral contraception, cimetidine, hormones in animal products, and conventional HRT for example. Endogenous oestrogens such as estradiol, estrone,
estriol, hydroxylated and methoxylated oestrogen metabolites, as well as oestrogens from enterohepatic recirculation, and their ratios could also be influenced by obesity, alcohol consumption, insulin resistance, and ageing. Alcohol consumption in particular, when combined with HRT, synergistically increases the risk of breast cancer24, 25
. Ageing and menopause, a high body
mass index (BMI), and the presence of inflammatory cytokines TNF-α, IL-1 and IL-6, increase the aromatase activity that converts androgens into oestrogens, increasing a local source of oestrogens that facilitates the growth of hormone responsive tumour cells. Oestrogen dominance as a result of hormonal imbalances between oestrogen, progesterone and testosterone can further complicate the oestrogen burden. Nutritional factors and dietary oestrogens can
influence receptor expression and modify SNP activity, affecting the detoxification pathways of oestrogen. This is a foundation of nutrigenetics that is used in patients with an unfavourable oestrogen metabolism genetically determined to modulate and improve detoxification.
Certain
nutrients can selectively alter gene expression involved in oestrogen metabolism, modifying the type and amount of oestrogen metabolites.
wt/wt wt/vt vt/vt X
X X
X X X X
xx PP
Genotype wt/wt: homozygous wild type wt/vt: heterozygous variant genotype vt/vt: homozygous variant genotype
Figure 5 Combination of genotypes GSTM1 and COMT with an increased risk for sporadic breast cancer (predictive activity of enzymes, absent and decreased)
Predictive activity N normal slightly increased increased strongly increased
slightly decreased decreased strongly decreased no activity
Genetic testing for increased HRT safety and personalised prevention Testing low penetrance genes involved in oestrogen metabolism are useful diagnostic tools to identify a patientÕs individual metabolic pathways, and to calculate the possible risk for breast cancer, as well as allowing physicians to tailor a personalised approach to HRT. None of these polymorphisms would significantly increase the risk of breast cancer on their own, but in the presence of prolonged oestrogen exposure or other relevant dietary and lifestyle risk factors, the risk for breast cancer is significantly increased26, 27
. Furthermore, a
combination of certain polymorphisms can increase the incidence of breast cancer (e.g. COMT in combination with GSTM1) (Figure 5). Laboratoires R• unis (Luxemburg) provides a
comprehensive genetic test (FEMgen) that can help to obtain a clear picture of SNPs present in a particular case, as well as their predictive activity. This test should be used as an additional tool to blood and urine samples (for oestrogen metabolites), medical history, lifestyle and diet. In cases of a presence of a combination of high-risk genotypes, a hormone substitution therapy will not be prescribed: not conventional HRT, and not even bioidentical HRT (BHRT; which is considered safer and more efficacious than synthetic counterparts)28
prime-journal.com | January/February 2013 ❚
N N
N
N
N
*Non-accepted parameter, carried out according to the Good Practice Guide of Analyses
Genotype Predictive activity
. In fact,
dietary and lifestyle changes, and botanicals as supplementation, would be prescribed to decrease the risk of hormone-sensitive cancers. This is often given
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