Chemically induced mammary gland tumorigenesis in the rat is the model system for studies of breast cancer. However, the mechanism(s) underlying this process by N-substituted aryl compounds has not been elucidated. Required for their carcinogenicity is oxidation to the N-hydroxy compounds which may then be activated by one electron oxidation (OEO) involving mammary gland peroxidase (MGP) to nitroxyl free radicals (NFR). Our proposed studies have 4 specific aims: 1) to establish whether susceptibilities to OEO of 4 isomeric N-fluorenylhydroxamic acids correlate with their tumorigenicities for the rat mammary gland: N-hydroxy-N-2-fluorenylacetamid (N-OH-2-FAA) Greater that N-OH-3-FAA is dominated by N-OH-1-FAA Greater than N-OH-4-FAA. It is anticipated that the less carcinogenic isomers will be oxidized to NFR, as are the carcinogenic isomers, but that the kinetic properties of each NFR will differ. Since these properties may determine if the NFR or its dismutation products, the nitrosofluorene and acetate ester of the hydroxamic acid, interact with cellular acceptors, rates of formation and dismutation of NFR and rates of product formation will be measured. Types of interactions with macromolecules with consideration of differing chemical reactivities of the isomeric products and specificities of acceptors in the susceptible (mammary gland) vs nonsusceptible (female rat liver) tissues will be determined; 2) to partially purify MGP and determine its subcellular localization, substrate specificity and estrogene-inducibility. If MGP is found to catalyze OEO of N-OH-2-(and -3-)FAA to NFR, the resulting interaction products with mammary gland nuclei (DNA adducts and acetylated chromatin) will be determined in vitro and in vivo. This will provide the most direct assessment of the role of MGP in activation of mammary gland carcinogens; 3) to determine whether rat mammary gland contains flavin-monooxygenase and can N-hydroxylate carcinogenic N-arylamines, and whether N-hydroxylamines undergo OEO by MGP to NFR. Since these NFR do not dismutate, their direct interactions with cellular acceptors will be investigated; and 4) to determine whether lactoperoxidase of lactating mammary gland or rat milk catalyzes OEO of N-OH-2-FAA to NFR, and to identify resultant interaction products with milk protein and lipid. These interactions may counteract the activation of N-OH-2-FAA by lactoperoxidase. These methodologies will be used: electron spin resonance and UV spectroscopy, gas and liquid chromatography, kinetic and computer analyses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028000-07
Application #
3167915
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1980-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Malejka-Giganti, Danuta; Bennett, Kristen K; Culp, Sandra J et al. (2005) Suppression of 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis by pre-initiation treatment of rats with beta-naphthoflavone coincides with decreased levels of the carcinogen-derived DNA adducts in the mammary gland. Cancer Detect Prev 29:338-47
Horn, Thomas L; Reichert, Mark A; Bliss, Robin L et al. (2002) Modulations of P450 mRNA in liver and mammary gland and P450 activities and metabolism of estrogen in liver by treatment of rats with indole-3-carbinol. Biochem Pharmacol 64:393-404
Ritter, Clare L; Culp, Sandra J; Freeman, James P et al. (2002) DNA adducts from nitroreduction of 2,7-dinitrofluorene, a mammary gland carcinogen, catalyzed by rat liver or mammary gland cytosol. Chem Res Toxicol 15:536-44
Ritter, C L; Prigge, W F; Reichert, M A et al. (2001) Oxidations of 17beta-estradiol and estrone and their interconversions catalyzed by liver, mammary gland and mammary tumor after acute and chronic treatment of rats with indole-3-carbinol or beta-naphthoflavone. Can J Physiol Pharmacol 79:519-32
Ritter, C L; Decker, R W; Malejka-Giganti, D (2000) Reductions of nitro and 9-Oxo groups of environmental nitrofluorenes by the rat mammary gland in vitro. Chem Res Toxicol 13:793-800
Malejka-Giganti, D; Niehans, G A; Reichert, M A et al. (2000) Post-initiation treatment of rats with indole-3-carbinol or beta-naphthoflavone does not suppress 7, 12-dimethylbenz[a]anthracene-induced mammary gland carcinogenesis. Cancer Lett 160:209-18
Brauze, D; Malejka-Giganti, D (2000) A novel 4 S [3H]beta-naphthoflavone-binding protein in liver cytosol of female Sprague-Dawley rats treated with aryl hydrocarbon receptor agonists. Biochem J 347 Pt 3:787-95
Malejka-Giganti, D; Niehans, G A; Reichert, M A et al. (1999) Potent carcinogenicity of 2,7-dinitrofluorene, an environmental pollutant, for the mammary gland of female Sprague-Dawley rats. Carcinogenesis 20:2017-23
Ritter, C L; Malejka-Giganti, D (1998) Nitroreduction of nitrated and C-9 oxidized fluorenes in vitro. Chem Res Toxicol 11:1361-7
Brauze, D; Crow, J S; Malejka-Giganti, D (1997) Modulation by beta-naphthoflavone of ovarian hormone dependent responses in rat uterus and liver in vivo. Can J Physiol Pharmacol 75:1022-9

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