Molecular and Cellular Basis of the Mammary Gland Susceptibility to Carcinogenesis

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 (3)H-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.