Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland.
Milk production during lactation is a consequence of the suckling stimulus and the presence of glucocorticoids, prolactin, and insulin. After weaning the glucocorticoid hormone level drops, secretory mammary epithelial cells die by programmed cell death and the gland is prepared for a new pregnancy. We studied the role of steroid hormones and prolactin on the mammary gland structure, milk protein synthesis, and on programmed cell death. Slow-release plastic pellets containing individual hormones were implanted into a single mammary gland at lactation. At the same time the pups were removed and the consequences of the release of hormones were investigated histologically and biochemically. We found a local inhibition of involution in the vicinity of deoxycorticosterone- and progesterone-release pellets while prolactin-release pellets were ineffective. Dexamethasone, a very stable and potent glucocorticoid hormone analogue, inhibited involution and programmed cell death 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 DNA binding activity and elevated c-fos, junB, and junD mRNA levels. Several potential target genes of AP-1 such as stromelysin-1, c-jun, and SGP-2 that are induced during normal involution were strongly inhibited in dexamethasone-treated animals. Our results suggest that the cross-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 programmed cell death in the postlactational mammary gland depends on functional AP-1.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D051152:Clusterin; D003169:Complement Inactivator Proteins / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004702:Endocrine Glands / Q000187:drug effects; D004847:Epithelial Cells; D005260:Female; D016758:Genes, jun / Q000502:physiology; D005938:Glucocorticoids / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000502:physiology; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D011374:Progesterone / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
C495243:Clu protein, mouse; D051152:Clusterin; D003169:Complement Inactivator Proteins; D005938:Glucocorticoids; D006023:Glycoproteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D018808:Transcription Factor AP-1; D011374:Progesterone; D003907:Dexamethasone; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3