Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis.

The susceptibility of the rat mammary gland to carcinogenesis decreases with aging and is nullified by pregnancy and lactation. This work was carried out to determine whether these differences in susceptibility to carcinogenesis are the result of variations in cell kinetics induced by both aging and parity. Cell cycle (Tc) and growth fraction (GF) were studied in the mammary gland epithelium of young virgin, old virgin, and parous Sprague-Dawley rats. For the study of Tc, five young virgin, five old virgin, and five parous rats received while in estrus an i.p. injection of 1.7 muCi [3H] thymidine per g body weight. Mammary gland biopsies were taken at 2-hr intervals for the first 24 hr and every 4 hr thereafter up to 72 hr. GF was determined in two young virgin, two old virgin, and two parous rats in which an osmotic minipump releasing 1 microCi [3H]thymidine per hr was implanted i.p. After 5 days, the animals were killed, and the mammary glands were removed. Mammary gland biopsies and whole glands were fixed in Bouin's fluid and embedded in paraffin. Deparaffinized sections were processed for autoradiography. The labeled mitosis wave, labeling index, and GF were determined. The results indicated that, in young virgin rats, mammary gland Tc was 9.9 hr in the most undifferentiated structures (terminal end buds), lengthening to 17.3 hr in terminal ducts (TD) and to 28.2 hr in alveolar buds (AB). In the mammary gland of old virgin rats, Tc was 18.75 hr in terminal ducts in regression, 20.57 hr in TD, and 30.75 hr in AB. In parous rats, mammary gland Tc was 23.9 hr in TD and 49.63 hr in AB. Lengthening of Tc in all of these structures was due to a lengthening of G1, while the duration of the other phases of the cell cycle remained unchanged. GF was 0.55 in terminal end buds of young virgin rats, decreasing to 0.39 and 0.13 in TD and AB, respectively. In terminal ducts in regression of old virgin rats, GF was 0.19, decreasing to 0.054 and 0.030 in TD and AB, respectively. In TD and AB of parous rat, mammary gland GF was 0.009 and 0.004, respectively. These results suggest that the high susceptibility to carcinogenesis that has been demonstrated in young virgin rats is due to the presence of a large proliferative compartment, mainly in terminal end buds and TD, while the low susceptibility of parous animals is due to the formation of a large compartment of nonproliferating cells, and that those cells still proliferating have a longer G1 than do those of young and old virgin rats.