Molecular and Cellular Basis of the Mammary Gland Susceptibility to Carcinogenesis

Abstract

Mammary carcinomas induced by the administration of 7,12-dimethylbenz(a)anthracene (DMBA) to young virgin rats arise from undifferentiated terminal ductal structures called terminal end buds (TEBs). TEBs that normally differentiate into alveolar buds (ABs) and lobules under the influence of DMBA develop intraductal proliferations which progress to carcinoma. The high susceptibility of the young virgin rat TEBs to neoplastic transformation is due to its large proliferative compartment, with cells cycling every 10 hr, and to a higher 3H-DMBA uptake. Progressive differentiation of TEBs into ABs and lobules or their regression to terminal ducts (TDs) is seen with aging. Complete differentiation of the gland is attained only through pregnancy and lactation. The greater differentiation of the gland is manifested as permanent structural changes, consisting in the disappearance of TEBs and in a diminution of the number of TDs due to their differentiation into ABs and lobules. This greater differentiation results in a diminished or total refractoriness of the gland to the carcinogen because ABs and lobules have a lower proliferative compartment and a longer cell cycle than TEBs and TDs. Cells of parous rats have both in vivo and in vitro a lower DMBA-DNA binding capacity, a lower DNA synthesis and a greater ability to repair DMBA damaged DNA than cells of young virgin rats. The more efficient DNA repair capacity of the parous rat mammary gland is demonstrated by the induction of unscheduled DNA synthesis and a removal of DMBA-DNA adducts.

Mammary gland neoplasia in long-term rodent studies.

“…Thus, the more differentiated the structure at the time of carcinogen administration, the more benign and organized is the lesion that develops (Fig. 12) (15,22,24,167). The similarities observed between benign lesions developed in the human breast and the rodent mammary gland ( Table 10) are indicative of a similarity in their pathogenetic pathways as well.…”

A mammary fibroadenoma with terminal end buds-like structures in a 7-week-old male SD rat

“…It is known that mammary tumors originating from the TEBs are induced by the administration of various carcinogens, including 7,12-Dimethylbenzo[a]anthracene (DMBA) 2,3,21,22 . However, mammary tumors induced by chemical carcinogens are generally adenocarcinomas, characterized by intraductal growth of neoplastic epithelial cells 21,22 . On the other hand, it has been reported that fibroadenomas occur when a more differentiated fraction, such as alveolar buds, becomes a tumor 21,22 .…”

“…However, mammary tumors induced by chemical carcinogens are generally adenocarcinomas, characterized by intraductal growth of neoplastic epithelial cells 21,22 . On the other hand, it has been reported that fibroadenomas occur when a more differentiated fraction, such as alveolar buds, becomes a tumor 21,22 . This case is unique in that it shows benign neoplastic growth rather than malignant growth, although TEB, which is an undifferentiated component of the mammary gland, resulted in neoplastic transformation.…”

“…It is difficult to compare with other cases because of the lack of detailed reports on mammary tumors in young animals, but this case resembled human juvenile fibroadenomas in terms of clinical signs. Tumors in humans have been reported as rare fibroadenomas and classified according to the characteristics of clinical signs; they occur more commonly in adolescent girls or young women and can be very large and grow rapidly 21 . Histologically, these tumors often show pericanalicular patterns, with stromal cells growing around open ducts in a circumferential fashion 23 .…”