Journal of Mammary Gland Biology and Neoplasia, Vol. 5, No. 4, 2000 Rat Models of Premalignant Breast Disease Henry J. Thompson 1,3 and Meenakshi Singh 2 While a number of agents have been shown to induce mammary carcinogenesis in the rat, pre- malignant stages of the disease have been best characterized in chemically-induced models, specifically those initiated by either 7,12 dimethylbenz[α]anthracene (DMBA) 4 or 1-methyl- 1-nitrosourea (MNU). In general, it appears that epithelial cells in mammary terminal end buds or terminal ductules are the targets of carcinogenic initiation, and that a series of mor- phologically identifiable steps are involved in the development of mammary carcinoma. The premalignant steps include ductal hyperplasia of the usual type and carcinoma in situ of the cribriform or comedo type; atypical ductal hyperplasia has not been reported. Thus the histo- genesis of lesions occurring in chemically induced mammary carcinogenesis in the rat is similar to that observed in the human; although, the spectrum of lesions observed in the rat is lim- ited. Opportunities to investigate the biological and molecular characteristics of premalignant breast disease in the rat are presented. KEY WORDS: Pre-malignancy; breast cancer; experimental model; rat. INTRODUCTION The increasing opportunities to target premalig- nant lesions in the prevention of breast cancer, as well as the importance of premalignant breast lesions in both risk assessment and in determining patient management options, makes the availability of ani- mal models to study this aspect of disease progression highly desirable. Fortunately, animal models for pre- malignant breast disease in the rat already exist, and have been characterized to various degrees over the last 40 years. Nonetheless, despite the availability of 1 Center for Nutrition in the Prevention of Disease, AMC Cancer Research Center, Lakewood, Colorado. 2 Department of Pathology, University of Colorado Health Sci- ences Center, Denver, Colorado. 3 To whom correspondence should be addressed to AMC Cancer Research Center, 1600 Pierce Street, Lakewood, Colorado 80214. E-mail: thompsonh@amc.org 4 Abbreviations: 1-methyl-1-nitrosourea (MNU); 7,12 dimethyl- benz[α] anthracene (DMBA); hyperplastic alveolar nodule (HAN); terminal ductule hyperplasia (TDH); hyperplastic termi- nal end buds (HEB); intraductal proliferation (IDP); terminal end bud (TEB); intraductal proliferation-initiated (IDP i ); intraductal proliferation-initiated and promoted (IDP ip ); ductal carcinoma in situ (DCIS); carcinoma in situ (CIS). such models, relatively little is known about the cellu- lar and molecular events underlying the pathogenesis of premalignant stages of mammary carcinogenesis in the rat. The intent of this paper is to describe an- imal models that are available, to summarize what is known about the occurrence of premalignant stages of the disease in these models, to indicate how prema- lignant disease in the rat compares with the human disease process, and to identify some of the critical gaps in knowledge of premalignant breast disease that could be investigated in the rat. HISTOPATHOGENESIS OF BREAST CANCER The sequential steps most commonly described in the natural history of breast cancer are: ductal hyper- plasia, atypical ductal hyperplasia, carcinoma in situ, and invasive carcinoma (1,2). Evidence will be pre- sented that the development of mammary carcinoma in the rat has a similar natural history (3,4). Thus we will focus our discussion on premalignant lesions ob- served in the human and the rat, although some con- sideration will also be given to preneoplastic lesions termed hyperplastic alveolar nodules which are not 409 1083-3021/00/1000-0409$18.00/0 C  2000 Plenum Publishing Corporation