The Mammary Gland Carcinogens: The Role of Metal Compounds and Organic Solvents Page: 4
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International Journal of Breast Cancer
stimulating factors through activating mitogenic signaling
pathways and inducing the expression of cellular protoonco-
gens. At the same time, modified gene expression can result
from epigenetic mechanism like hypo- or hypermethylation
of DNA and/or disturbed histone acetylation. The other way
the carcinogenic metals can alter mammalian cell growth is
by inactivating growth control mechanism . In general,
the deregulation of cell proliferation that leads to tumor
growth and invasive cancer stage is often imposed by viral
agents, heavy metals, toxins, and oxidants. Some metal car-
cinogens have been shown to inactivate the tumor suppressor
proteins p53. Metal ions can also deregulate cell proliferation
by inactivating apoptotic process resulting in adaptation to
the cytotoxicity of the metal.
4. Specific Metal Mammary Gland Carcinogens
4.1. Arsenic. Arsenic is commercially produced as a byprod-
uct of nonferrous metal production, precisely from copper
smelting. Arsenic exposure constitutes one of the most wide
spread environmental carcinogens associated with numerous
cancers. Arsenites are found in drinking water, some wood
preservatives, insecticides, and herbicides. In the natural
waters, arsenic occurs in oxidation states III and V in the
form of arsenous acid (H3AsO3) and arsenic acid (H3AsOs)
and their salts ; at the same time smaller amounts of
monomethylarsonic acid (MMA) and dimethylarsinic acid
(DMA) can also be present. The trivalent monomethylated
(MMAIII) and dimethylated (DMAIII) arsenic species have
been detected in lake water . The International Agency
of Research on Cancer (IARC) in its evaluations classified
arsenic and its compounds as highly carcinogenic to humans
. Among the cancers linked to arsenic compounds are
skin, bladder, liver, kidney, lung and breast cancers .
The main source of exposure to humans is through drink-
ing ground water with high level of arsenic contamination
especially in South Asia region. This region witnessed wide
spread carcinogenic effects from the contaminated water
that led USEPA to declare the maximum contaminant limit
to 0.010 mg/L in line with WHO guidelines . The rice
planted by irrigation in these regions has also, through
uptake, introduced arsenic into the human food. Among
other major exposure mechanisms of arsenic to human food
is through consumption of contaminated fish and sea foods.
These exposure mechanisms can be easily reduced through
effective food evaluation by authorities and enhanced edu-
cation to the populations in the regions affected, alongside
minimizing industrial exposures.
Various methods have been developed and improved for
the measurement of total arsenic exposure agents especially
foods and drinking water and have been widely used for
the evaluation of the quantitative or qualitative level of
contamination and the resulting concentrations of arsenic in
humans. Similarly, analytical methods allowing arsenic speci-
ation have attracted more research in light of its carcinogenic
potential. The form of existence of the arsenic compounds
dictates its environmental fate and behavior, bioavailability,
and toxicity, for instance, the inorganic AsIII and AsV are far
more toxic than MMA and DMA .
Arsenic trioxide (As203) which has been used as a
component of Chinese medicine for hematologic malignancy
treatment induces cell cycle arrest and apoptosis in solid
tumors including breast cancer . It is hoped that new
insights into how the As203 binds to specific receptors
and how they trigger signaling pathways may help explain
its anticancer strategies that may be helpful in the treat-
ment of other solid tumors including breast cancer. High
environmental concentration and thus exposure of arsenite
(5 M/0.65 mg/L) can induce both replications-dependent
DNA double-strand breaks and homologous recombination.
The study found that the double-strand break was replication
dependent which might have resulted from conversion of a
DNA single-strand break to double-strand break . On
the other hand, low arsenite concentration induces ROS
production and ROS depolarization of the mitochondria
membrane. When the ROS mediated DNA damage was
measured by the presence of 8-OHdG DNA adducts in the
nuclei, IKB phosphorylation, NF-KcB activation, and increase
in c-Myc and HO-1 protein levels were observed. The role
of arsenic induced breast cancer cell, MCF-7, recruitment
into the S-phase of cell cycle and cell proliferation can be
explained by the above factors. The study, however, concluded
that arsenates activates many pathways involved in MCF-
7 cell proliferation leading to a suggestion that arsenite
exposure may be a high risk cause to breast cancer .
Accumulating evidence from cell culture studies and from
arsenic exposed humans suggests that arsenic changes the
DNA methylation pattern, hence affecting the expression of
oncogenes and tumor suppressor genes.
4.2. Cadmium. Cadmium is emitted to the air by mines,
metal smelters, and industries which use cadmium com-
pounds for in the production of alloys, batteries, pigments,
and plastics . It is a widespread environmental pollutant
that has been declared carcinogenic to humans by the
International Agency of Cancer Research . Both active
and passive smoking of all forms of tobacco is the single
most means of exposure to humans, since all forms of
tobacco contain high levels of cadmium. This is so since
the absorption of cadmium in tobacco smoke from the
lungs into the body cells is much greater than the gastroin-
testinal tract absorption [41, 42]. It is important to note
that tobacco also contains other 16 carcinogenic compounds
apart from cadmium, including benzo[a]pyrene (BaP), 4-
(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) and
N'-nitrosonornicotine (NNN), 2-naphthylamine, 4-aminob-
iphenyl, formaldehyde, 1,3-butadiene, benzene, vinyl chlo-
ride, ethylene oxide, arsenic, beryllium, nickel compounds,
chromium VI, and polonium-210 which have been classified
by IARC as group 1 carcinogens . Since cadmium ions can
easily be absorbed and stored in plants roots, stems, leaves
and fruits, consumption of such affected parts of plants by
animals may lead to contamination of their milk and meat
products, which in effect can contaminate human food .
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Mulware, Stephen Juma. The Mammary Gland Carcinogens: The Role of Metal Compounds and Organic Solvents, article, April 24, 2013; [Nasr City, Cairo]. (digital.library.unt.edu/ark:/67531/metadc330563/m1/4/: accessed October 17, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.