Biomedical Engineering Reference
In-Depth Information
which the cells are exposed. Examples include how well metabolizing enzymes
function to modulate drug and hormone activity (pharmacogenomics) as well as
how well a hormone such as testosterone binds to the androgen receptor based
on the number of CAG repeats in the promoter region (7). In addition, before the
damaging agent can cause mutation, it must evade extrinsic risk modulators.
Extrinsic risk modulators are best characterized by chemoprevention agents such
as antioxidants. Dietary factors such as selenium and vitamin E have been dem-
onstrated to remove damaging oxygen radicals from the intracellular environ-
ment by catalyzing their breakdown to water (8,9). If the damaging agent
escapes all of these potential protective mechanisms, it still must damage the
DNA in a susceptible place that will allow a survival advantage (2,4). Most mu-
tations to the DNA are either deleterious or neutral—very few are adaptive (1).
In bacteria, for example, it is estimated that only one in 10,000 mutations pro-
vide an adaptive advantage (1,10). It is probable that this ratio would be greatly
higher for the much more complex human genome.
These gene-environment interactions that contribute to cancer can be un-
derstood in the context of any number of evolutionary paradigms (Table 1). In
breast cancer, a woman may inherit a mutation in the allele that contains BRCA-
1, a gene important in maintaining normal breast cell function. This starts the
Table 1
. Comparison of cancer cells and members of an animal herd:
an evolution/natural selection paradigm
Examples of contributors to
Examples of contributors
successful selection and
to mutations in
evolution in individual
cancer cells
members of a herd
Susceptibility allele
Loss of BRCA1: increases
Loss of gene to
chance of developing
make horns
breast cancer
Exposures
Diet, carcinogens, radiation,
Predators, weather, diet,
viruses, microbes,
viruses, microbes,
inflammation, chemicals,
water supply
hormones
Intrinsic modulators
Drug metabolizing
Length of legs, strength
pathways
of muscles
Extrinsic modulators
Antioxidants, cancer
Size of the herd, place in
screening, i.e.,
the herd when attacked,
PAP smears
ability of the herd to
migrate in response to
changes in environment
