GLUCOCORTICOID AND PROGESTERONE INHIBIT INVOLUTION AND PROGRAMMED CELL-DEATH IN THE MOUSE MAMMARY-GLAND

Milk production during lactation is a consequence of the suckling stim ulus and the presence of glucocorticoids, prolactin, and insulin. Afte r weaning the glucocorticoid hormone level drops, secretory mammary ep ithelial cells die by programmed cell death and the gland is prepared for a new pregnancy. We studied the role of steroid hormones and prola ctin on the mammary gland structure, milk protein synthesis, and on pr ogrammed cell death. Slow-release plastic pellets containing individua l hormones were implanted into a single mammary gland at lactation. At the same time the pups were removed and the consequences of the relea se of hormones were investigated histologically and biochemically. We found a local inhibition of involution in the vicinity of deoxycortico sterone- and progesterone-release pellets while prolactin-release pell ets were ineffective. Dexamethasone, a very stable and potent glucocor ticoid hormone analogue, inhibited involution and programmed cell deat h in all the mammary glands, It led to an accumulation of milk in the glands and was accompanied by an induction of protein kinase A, AP-1 D NA binding activity and elevated c-fos, junB, and junD mRNA levels. Se veral potential target genes of AP-1 such as stromelysin-1, c-jun, and SGP-2 that are induced during normal involution were strongly inhibit ed in dexamethasone-treated animals. Our results suggest that the cros s-talk between steroid hormone receptors and AP-1 previously described in cells in culture leads to an impairment of AP-1 activity and to an inhibition of involution in the mammary gland implying that programme d cell death in the postlactational mammary gland depends on functiona l AP-1.