Submitted to: Biology of Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/11/2001
Publication Date: 12/11/2001
Citation: CAPUCO, A.V., LI, M., LONG, E., REN, S., HRUSKA, K.S., SCHORR, K., FURTH, P.A. CONCURRENT PREGNANCY RETARDS MAMMARY INVOLUTION:EFFECTS ON APOPTOSIS AND PROLIFERATION OF THE MAMMARY EPITHELIUM AFTER FORCED WEANING OF MICE. BIOLOGY OF REPRODUCTION. vol. 66, pp. 1471-1476, 2002. Interpretive Summary: At the conclusion of lactation, regression of the mammary gland occurs. However, in dairy cows mammary regression is limited perhaps because they are typically pregnant at the time that milking is terminated. This experiment evaluated the effect of pregnancy on mammary involution in mice. When mice were simultaneously pregnant at when pups were weaned, mammary involution was limited. Pregnancy enhanced division of existing mammary cells and inhibited the initiation of programmed cell death. Pregnancy maintained or initiated the signaling pathways of two hormones that regulate mammary gland function. When mice were pregnant at the time of weaning, the prolactin signaling pathway (Stat5a activation) in mammary gland was maintained. Furthermore, pregnancy instated the signaling pathway (progesterone receptor) for progesterone that is typically absent in mammary gland of lactating mice. Of key genes that regulate programmed cell death (apoptosis), pregnancy increased the expression of a gene (bfl-1) in mammary tissue that promotes the survival of cells. The data indicate that pregnancy inhibits mammary cell death after weaning while permitting proliferation of mammary cells, and support the hypothesis that prolactin and progesterone signaling pathways act in concert to mediate this effect.
Technical Abstract: The effect of pregnancy on post-weaning mammary gland involution was investigated in mice. On the third day after forced weaning at lactation day 10, the apoptotic index was 56% lower in mammary tissue of mice that were pregnant at the time of weaning than in non-pregnant mice. Conversely, the bromodeoxyuridine labeling index was increased seven-fold in pregnant mice compared to non-pregnant controls (3.5% vs. 0.5%). Structure of mammary alveoli was largely maintained in post-weaning pregnant mice. The effect of pregnancy on three specific mammary epithelial cell survival pathways was examined. First, pregnancy blocked the loss of Stat5a phosphorylation during involution. Significantly, loss of Stat5a phosphorylation during involution was not correlated with loss of Stat5a nuclear localization. Second, pregnancy maintained nuclear localized progesterone receptor during lactation. Third, pregnancy was associated with increased expression of bfl-1 during involution but had little effect on expression of other bcl-2 family members. The data indicate that pregnancy inhibits mammary cell apoptosis after weaning while permitting proliferation of the mammary epithelium, and support the hypothesis that Stat5a and progesterone signaling pathways act in concert to mediate this effect.