It has been demonstrated that in humans certain factors such as early menarche, late pregnancy, and nulliparity are associated with a higher risk of developing breast cancer, while early pregnancy acts as a protective factor. Induction of mammary cancer in rats by administration of the chemical carcinogen 7, 12-dimethylbenz(a)anthracene reveals that the same factors influencing human breast cancer risk also affect the susceptibility of the rat mammary gland to the chemical carcinogen. Nulliparous rats and rats undergoing pregnancy interruption are more susceptible to developing carcinomas. This fact has been attributed to the incomplete differentiation of the gland at the time of carcinogen administration. Parous rats are resistant to the carcinogenic effect of DMBA, which is explained by the complete development of the gland attained during pregnancy and lactation. This development is manifested by the differentiation of terminal end buds into secretory units, which have a smaller proliferative compartment; the epithelial cells of these secretory units have a longer cell cycle, less avidity for binding DMBA, and possess a more efficient DNA excision repair capacity.

Differentiation of the mammary gland and susceptibility to carcinogenesis

Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model.

As the result of rapidly developing technological advances, our understanding of the biotransformation and bioactivation of 7, 12-DMBA has increased markedly in recent years. In terms of the metabolic conversion of this polynuclear aromatic hydrocarbon to reactive mutagen/carcinogens, the "bay region" generalization appears to apply, although the candidacy of a number of other intermediary metabolites as ultimate biologically-active forms still remains viable. Large gaps remain in knowledge concerning the nonoxidative metabolic transformations of 7, 12-DMBA, and these require closing in order to further our understanding of the regulation of mechanics controlling steady-state levels of reactive intermediates. Studies on the photooxidation of the hydrocarbon have allowed a stronger appreciation of its chemical reactivity and instability and promise to help resolve many of the apparently conflicting observations of the past. 7, 12-DMBA remains a highly interesting and valuable tool in investigations of bioactivation processes as they relate to the etiology of several important pathologic conditions, including chemically induced tissue necrosis, mutagenesis, carcinogenesis, teratogenesis, atherogenesis, and, possibly, other pathogenic phenomena as well. It is hoped that this review will serve to benefit research in these areas and hasten the reduction of such pathologic phenomena in our society.

Biotransformation and bioactivation of 7,12-dimethylbenz[a]anthracene (7,12-DMBA)

Mixed function oxidase activities in lactating rats and their offspring following dietary exposure to polybrominated biphenyls

This is the second Special Issue addressing the diversity and use of animal models of breast cancer. The previous issue (Breast Cancer Res Treat 39:1-135, 1996), dealt with a variety of topics such as the characteristics of chemically- and virally-induced rodent models, immunobiologies of immunedeficient mice, transgenic mouse models, and models of metastasis. In the first part of this second Special Issue, the articles address animal models for studying life-style factors, including psychosocial, exercise, and nutritional research in breast cancer. In the second section, there is emphasis on the controversial area of dietary fat, with other authors addressing caloric restriction and dietary isoflavonoids, retinoids, and monoterpenes in the third part. In the final section, a series of authors provide suggestions for approaching various issues involving experimental design, including nutritional studies, drug screening models, statistical considerations, quantitation of tumor growth kinetics, and animal husbandry. These articles, and some additional issues raised during the previous Special Issue, are briefly discussed in this overview. They include a further evaluation of the relative merits of 7,12-dimethylbenz(a)anthracene and N-nitroso-N-methylurea as carcinogens, and of the use of the AIN76 and AIN93 semipurified diets in studies of mammary carcinogenesis.

Animal models of breast cancer: experimental design and their use in nutrition and psychosocial research.

The metabolism of 7,12-dimethylbenz(a)anthracene to hydroxymethyl derivatives differs in hepatic and mammary tissue homogenates. Countercurrent distribution and carrier recrystallization have been shown to be effective additional tools in the identification of 7-hydroxymethyl-12-methylbenz(a)anthracene, 12-hydroxymethyl-7-methylbenz(a)anthracene, and 7,12-dihydroxymethylbenz(a)anthracene. In the hepatic tissue, 7,12-dimethylbenz(a)anthracene is transformed into all three of these metabolites whereas the mammary gland formed only the monohydroxy compounds. Pretreatment of rats with 3-methylcholanthrene induces a marked increase in 7,12-dimethylbenz(a)anthracene-metabolizing enzymes in the liver causing further conversion of the 7-hydroxymethyl-12-methylbenz(a)anthracene, 12-hydroxymethyl-7-methylbenz(a)anthracene, and 7,12-dihydroxy-7,12-dimethylbenz(a)anthracene to more polar components. In contrast, mammary gland caused a diminution but still detectable level of the carcinogenic 7-hydroxymethyl-12-methylbenz(a)anthracene and a noticeable increase in the conversion to 12-hydroxymethyl-7-methylbenz(a)anthracene. The data illustrate, for the first time, the ability of the mammary tissue to metabolize 7,12-dimethylbenz(a)anthracene.

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Thecla S. Tamulski

Papers

Comparative Metabolism of 7,12-Dimethylbenz(a)anthracene in Liver and Mammary Tissue