Elucidation of
estrogen carcinogenesis required a few fundamental discoveries made by studying the mechanism of
carcinogenesis of
polycyclic aromatic hydrocarbons (PAH). The two major mechanisms of metabolic activation of PAH involve formation of radical
cations and diol
epoxides as ultimate carcinogenic metabolites. These intermediates react with
DNA to yield two types of adducts: stable adducts that remain in
DNA unless removed by repair and depurinating adducts that are lost from
DNA by cleavage of the glycosyl bond between the
purine base and
deoxyribose. The potent carcinogenic PAH
benzo[a]pyrene,
dibenzo[a,l]pyrene, 7,12-dimethylbenz[a]
anthracene and
3-methylcholanthrene predominantly form depurinating
DNA adducts, leaving apurinic sites in the
DNA that generate
cancer-initiating mutations. This was discovered by correlation between the depurinating adducts formed in mouse skin by treatment with
benzo[a]pyrene,
dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]
anthracene and the site of mutations in the Harvey-ras oncogene in mouse skin
papillomas initiated by one of these PAH. By applying some of these fundamental discoveries in PAH studies to
estrogen carcinogenesis, the natural
estrogens estrone (E1) and
estradiol (E2) were found to be mutagenic and carcinogenic through formation of the depurinating
estrogen-
DNA adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. These adducts are generated by reaction of
catechol estrogen quinones with
DNA, analogously to the
DNA adducts obtained from the
catechol quinones of
benzene,
naphthalene, and the
synthetic estrogens diethylstilbestrol and
hexestrol. This is a weak mechanism of
cancer initiation. Normally,
estrogen metabolism is balanced and few
estrogen-
DNA adducts are formed. When
estrogen metabolism becomes unbalanced, more
catechol estrogen quinones are generated, resulting in higher levels of
estrogen-
DNA adducts, which can be used as
biomarkers of unbalanced
estrogen metabolism and, thus,
cancer risk. The ratio of
estrogen-
DNA adducts to
estrogen metabolites and conjugates has repeatedly been found to be significantly higher in women at high risk for
breast cancer, compared to women at normal risk. These results indicate that formation of
estrogen-
DNA adducts is a critical factor in the etiology of
breast cancer. Significantly higher adduct ratios have been observed in women with breast, thyroid or
ovarian cancer. In the women with
ovarian cancer, single nucleotide polymorphisms in the genes for two
enzymes involved in
estrogen metabolism indicate risk for
ovarian cancer. When polymorphisms produce high activity
cytochrome P450 1B1, an activating
enzyme, and low activity
catechol-O-methyltransferase, a protective
enzyme, in the same woman, she is almost six times more likely to have
ovarian cancer. These results indicate that formation of
estrogen-
DNA adducts is a critical factor in the etiology of
ovarian cancer. Significantly higher ratios of
estrogen-
DNA adducts to
estrogen metabolites and conjugates have also been observed in men with
prostate cancer or
non-Hodgkin lymphoma, compared to healthy men without
cancer. These results also support a critical role of
estrogen-
DNA adducts in the initiation of
cancer. Starting from the perspective that unbalanced
estrogen metabolism can lead to increased formation of
catechol estrogen quinones, their reaction with
DNA to form adducts, and generation of
cancer-initiating mutations, inhibition of
estrogen-
DNA adduct formation would be an effective approach to preventing a variety of human
cancers. The dietary supplements
resveratrol and
N-acetylcysteine can act as preventing
cancer agents by keeping
estrogen metabolism balanced. These two compounds can reduce the formation of
catechol estrogen quinones and/or their reaction with
DNA. Therefore,
resveratrol and
N-acetylcysteine provide a widely applicable, inexpensive approach to preventing many of the prevalent types of human
cancer.