• The BCRL at Fox Chase Cancer Center from 1991 to the present
• Seminal work performed in the BCRL from 1972 to 1991
• Accomplishments
• Translational Research at the BCRL
• Recent Accomplishments
• Conferences and Lectures

Seminal work performed in the BCRL from 1972 to 1991

B. Chemically induced mammary carcinogenesis

Whereas hormone dependency has been an important area of research at the BCRL, the lab has also considered it relevant to devote attention to understanding how environmental carcinogens, such as polycyclic hydrocarbons, interact with the mammary epithelia of rodents and humans, and what mechanisms are activated for the causation of breast cancer. These studies, in both rodents and humans, have led to the conclusion that the carcinogenic potential of a given chemical is in great part modulated by the biological conditions of the target organ which determines its susceptibility to neoplastic transformation.

The BCRL has demonstrated that the induction of mammary carcinomas in the rat requires that a carcinogen act on a specific compartment of the mammary gland, the terminal end bud (TEB), a club-shaped undifferentiated structure found at the peripheral margins of the developing mammary parenchyma in young virgin rats (Figures 3 a,b, c: Click to see and Figures 4 a,b: Click to see). Although TEBs are present in the six pairs of mammary glands, tumor development does not occur randomly. Tumor incidence in animals treated with a carcinogen between the ages of 20 and 180 days is greater in those glands located in the thoracic region, whereas glands located in the abdominal and inguinal areas develop a lower number of tumors (Figure 5: Click to see). In addition to differences in tumor incidence as a consequence of the topographic location of the gland, there are differences in tumor type, which seem to vary with the age of the animal at the time of carcinogen treatment. Ductal and papillary adenocarcinomas are more frequent in both thoracic and abdominal glands of younger animals, whereas adenocarcinomas with tubular pattern are found mostly in abdominal glands of older animals. The development of the rat mammary gland occurs through a combined process of branching and differentiation of the parenchyma, mainly in those ducts ending in TEBs that progressively divide and differentiate into alveolar buds (ABs) (Figure 3: Click to see and Figure 6: Click to see). These structures in turn differentiate into lobules.

Figure 3: Whole mount preparation of the abdominal mammary gland (a) 21 days of age. (b) 35-days of age. (c) 55days of age. Toluidine blue x10.

Figure 4: Whole mount of abdominal rat mammary gland (a) Control. (b) After 35 days of DMBA administration. Toluidine blue, x4.

Figure 5: Drawing of a rat showing the distribution of the six pair of mammary glands. The fourth pair, or abdominal mammary gland, is the most frequently utilized for morphological, cell kinetics, and tumorigenic studies because of its large size and ease of access. However, they are less susceptible to be transformed by chemical carcinogens, as indicated in the histogram at the right hand side, which shows that the higher incidence of adenocarcinomas occurs in thoracic mammary glands in those animals inoculated with the carcinogen at ages younger than 100 days. These results were obtained by inoculating virgin Sprague Dawley rats intragastrically (ig) with a single dose of 8 mg 7, 12-dimethylbenz(a)anthracene (DMBA) (Sigma Chemical Co., St. Louis, MO) per 100 g body weight (bw). The carcinogen was dissolved in corn oil at a concentration of 16 mg DMBA/ml by heating in a water bath at 95oC for 30 minutes.

Figure 6:Whole mount of the TEB of the rat mammary gland at 45 days of age stained with toluidine blue x20. (b) Histological section at the tip of (a), stained with H&E, x40; (c) Lobule type 3 of a pregnant rat mammary gland stained with toluidine blue x20; (d) Histological section of (c) stained with H&E, x40

Although this pattern of development is common to the six pairs of mammary glands, it does not occur simultaneously in all of them, rather varies in relation to the topographic location of each specific pair. Individual structures, (i.e., TEBs, ABs, and lobules) appear similar in morphology in all the glands, however, their relative number and the general architecture of the organ vary notably from one pair of glands to another. The most notable ones are the thoracic mammary glands, since each single gland is composed of two different layers separated by connective and muscular tissue; one layer is composed of more numerous ABs and small lobules, whereas the adjacent one is more extensive and contains thin long ducts ending in prominent TEBs. The abdominal glands have a markedly reduced number of TEBs, which are located exclusively in the most distal portion of the gland; whereas the middle and proximal portions show a much more differentiated appearance. The difference in number of TEBs in thoracic versus abdominal mammary glands is significant. With aging, TEBs decrease progressively and their reduction is proportional in all the glands. This reduction is mostly due to either their regression to Terminal Ducts, or TDs, or to a greater differentiation to ABs and lobules. The higher incidence in ductal carcinomas observed in thoracic glands is attributed to the difference in degree of development of the undifferentiated layer of this gland in comparison to the glands located in other topographic areas.

This seminal work, undertaken by the BCRL, opened the gateway to developing new concepts in the understanding of the susceptibility of the mammary gland to carcinogenesis. Concepts such as  the role of differentiation and rate of cell proliferation of the mammary gland at the time of exposure to a given chemical carcinogen on its binding, DNA repair and tumor incidence, have influenced the way in which the study of mammary cancer is focused by researchers worldwide (J Natl Cancer Inst 59: 435, 1977; 61: 1451, 1978; Am J Pathol 96: 721, 1979; Cancer Res 40: 2677, 1980; Carcinogenesis 2:1327, 1981).