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Raloxifene and Desmethylarzoxifene Block Estrogen- Induced Malignant Transformation of Human Breast Epithelial Cells

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posted on 16.03.2012 by Irida Kastrati, Praneeth D. Edirisinghe, L-P-Madhubani P. Hemachandra, Chandrasena Chandrasena, Jaewoo Choi, Yue-Ting Wang, Judy L. Bolton, Gregory R. J. Thatcher
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.




This work was supported by the University of Illinois at Chicago (UIC) Graduate College Deiss Award in Biomedical Research to Irida Kastrati, UIC Graduate College fellowship, by National Institutes of Health grants R01 CA130037 (JLB) and R01 CA102590 (GRJT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Publisher Statement

Copyright: 2011 Kastrati et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. doi:10.1371/journal.pone.0027876


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