Basis of cellular autonomy in the susceptibility to carcinogenesis.
This paper summarizes our contributions in the basic understanding of the different susceptibility of the mammary gland to carcinogenesis according to age and parity history. Mammary carcinomas induced by the administration of 7,12-dimethylbenz-(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 hours, 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 through pregnancy and lactation or through exogenous administration of chorionic gonadotrophin. 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 lower DMBA-DNA binding capacity, lower DNA synthesis and 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.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D006063:Chorionic Gonadotropin / Q000008:administration & dosage / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004260:DNA Repair; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D006063:Chorionic Gonadotropin; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA