Prolonged exposure to estrogens is actively involved in the development of breast cancers. Available data suggest that the mechanism behind the formation of tumors by estrogens is complex and not well understood. An important part in estrogen-induced carcinogenesis is the growing awareness that reactive oxygen species may serve as signaling agents in carcinogenic pathways. The proposed study seeks to establish the molecular mechanism(s) underlying the role of oxidative stress in estrogen-induced carcinogenesis in an animal model relevant to human breast cancers - namely, the female ACI rat model of estrogen-induced breast cancer - and, by using the human breast epithelial cell line MCF-10F, thus establish the importance of oxidative stress in estrogen-induced breast cancer. Therefore, the investigators will characterize: the role of estrogen metabolism-mediated oxidative stress (Specific Aim 1); the role of estrogen receptors (ERs) in the generation of oxidative stress (Specific Aim 2); the role of oxidative stress in modifying ER-dependent gene regulation (Specific Aim 3); and, the role cytochrome P450 1B1 in estrogen-induced oxidative stress and subsequent carcinogenesis (Specific Aim 4). To accomplish Specific Aims 1-4, rats will be treated with estrogens, anti-estrogens, antioxidants, or with inhibitors of metabolic activation. In in vitro approaches, MCF-10F cells will be genetically manipulated with gene insertions and gene knockouts. These cell lines will then be treated with estrogens, anti-estrogens, antioxidants or inhibitors of metabolic activation to study the roles of estrogen receptors and antioxidant defense genes in the regulation of estrogen-dependent oxidant stress. Treatment of animals will be for seven months and information obtained from groups of animals that have been sacrificed at earlier times will be used to study changes during early treatment periods, as well as during both preneoplastic and neoplastic phases of development. Tumor incidence and histopathology will be characterized. Markers of oxidative stress as well as levels of antioxidant defense enzymes will be quantified both in the target organ breast and the nontarget organ liver; also, expression and regulation of estrogen-estrogen receptor-dependent genes will be quantified. Given the federal register's recent inclusion of estrogens as human carcinogens, the proposed studies have a great potential in the development of therapeutic strategies for the treatment of estrogen-induced neoplasia. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Poland, Alan P
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Columbia University (N.Y.)
Public Health & Prev Medicine
Schools of Public Health
New York
United States
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Ronghe, Amruta; Chatterjee, Anwesha; Singh, Bhupendra et al. (2016) 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors ? and ? in breast cancer cells. Toxicol Appl Pharmacol 301:1-13
Chatterjee, Anwesha; Ronghe, Amruta; Singh, Bhupendra et al. (2014) Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC b-Zip transcription factors in estrogen-induced breast carcinogenesis. J Biochem Mol Toxicol 28:529-38
Singh, Bhupendra; Shoulson, Rivka; Chatterjee, Anwesha et al. (2014) Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways. Carcinogenesis 35:1872-80
Ronghe, Amruta; Chatterjee, Anwesha; Singh, Bhupendra et al. (2014) Differential regulation of estrogen receptors ? and ? by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog. J Steroid Biochem Mol Biol 144 Pt B:500-12
Singh, Bhupendra; Chatterjee, Anwesha; Ronghe, Amruta M et al. (2013) Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer. BMC Cancer 13:253
Singh, Bhupendra; Ronghe, Amruta M; Chatterjee, Anwesha et al. (2013) MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis. Carcinogenesis 34:1165-72
Singh, Bhupendra; Bhat, Hari K (2012) Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer. Carcinogenesis 33:2601-10
Singh, Bhupendra; Bhat, Nimee K; Bhat, Hari K (2012) Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer. Carcinogenesis 33:156-63
Singh, Bhupendra; Bhat, Nimee K; Bhat, Hari K (2011) Partial inhibition of estrogen-induced mammary carcinogenesis in rats by tamoxifen: balance between oxidant stress and estrogen responsiveness. PLoS One 6:e25125
Jin, Mengyao; Arya, Priyanka; Patel, Kalpeshkumar et al. (2011) Effect of alcohol on drug efflux protein and drug metabolic enzymes in U937 macrophages. Alcohol Clin Exp Res 35:132-9

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