There is association between exposure to
estrogens and the development and progression of
hormone-dependent gynecological
cancers. Chemical
carcinogenesis by
catechol estrogens derived from oxidative metabolism is thought to contribute to
breast cancer, yet exact mechanisms remain elusive. Malignant transformation was studied in MCF-10A human mammary epithelial cells, since
estrogens are not proliferative in this cell line. The human and equine
estrogen components of
estrogen replacement therapy (ERT) and their
catechol metabolites were studied, along with the influence of co-administration of
selective estrogen receptor modulators (
SERMs),
raloxifene and
desmethyl-arzoxifene (DMA), and
histone deacetylase inhibitors. Transformation was induced by human
estrogens, and selectively by the 4-OH
catechol metabolite, and to a lesser extent by an equine
estrogen metabolite. The observed
estrogen-induced upregulation of CYP450 1B1 in
estrogen receptor negative MCF-10A cells, was compatible with a causal role for 4-OH
catechol estrogens, as was attenuated transformation by CYP450 inhibitors.
Estrogen-induced malignant transformation was blocked by
SERMs correlating with a reduction in formation of nucleobase
catechol estrogen (NCE) adducts and formation of
8-oxo-dG. NCE adducts can be formed consequent to
DNA abasic site formation, but NCE adducts were also observed on incubation of
estrogen quinones with free
nucleotides. These results suggest that NCE adducts may be a
biomarker for cellular electrophilic stress, which together with
8-oxo-dG as a
biomarker of oxidative stress correlate with malignant transformation induced by
estrogen oxidative metabolites. The observed attenuation of transformation by
SERMs correlated with these
biomarkers and may also be of clinical significance in
breast cancer chemoprevention.