The Mineralocorticoid Receptor May Compensate for the Loss of the Glucocorticoid Receptor at Specific Stages of Mammary Gland Development

Abstract

To study the role of glucocorticoid receptor (GR) at different stages of mammary gland development, mammary anlage were rescued from GR-/- mice by transplantation into the cleared fat pad of wild-type mice. In virgin mice, GR-/- outgrowths displayed abnormal ductal morphogenesis characterized by distended lumena, multiple layers of luminal epithelial cells in some regions along the ducts, and increased periductal stroma. In contrast, the loss of GR did not result in overt phenotypic changes in mammary gland development during pregnancy, lactation, and involution. Surprisingly, despite the known synergism between glucocorticoids and prolactin in the regulation of milk protein gene expression, whey acidic protein and beta-casein mRNA levels were unaffected in GR-/- transplants as compared with wild-type transplants. That mineralocorticoid receptor (MR) might compensate for the loss of GR was suggested by the detection of MR in the mammary gland at d 1 of lactation. This hypothesis was tested using explant cultures derived from the GR-/- transplants in which the mineralocorticoid fludrocortisone was able to synergistically induce beta-casein gene expression in the presence of prolactin and insulin. These studies suggest that MR may compensate for the absence of GR at some, but not at all stages of mammary gland development.

Regulation of Mammary Development as It Relates to Changes in Milk Production Efficiency

“…In addition, the glucocorticoid receptor has been observed to interact with PRL-activated STAT5 molecules to enhance the action of PRL in inducing -casein gene expression . Surprisingly, however, local expression of glucocorticoid receptor was not critical for normal function during lactogenesis and lactation of mice (Kingsley-Kallesen et al, 2002). Therefore, although glucocorticoids enhance the action of PRL during lactogenesis, their direct action on the mammary gland is not essential for normal lactation in rodents.…”

Impaired Alveologenesis and Maintenance of Secretory Mammary Epithelial Cells in Jak2 Conditional Knockout Mice

“…Biotinylated or Alexa Fluor 488-conjugated secondary antibodies were used to detect the phosphorylated and/or inactive form of Stat5. The labeling of apoptotic nuclei with ChromaTide Alexa Fluor 488-5-dUTP was performed as described previously (19). Slides were counterstained briefly with DAPI (4Ј,6Ј-diamidino-2-phenylindole) or hematoxylin to visualize nuclei.…”

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

“…Prior to the creation of a tissue-specific model of glucocorticoid action in mammary epithelial cells, researchers utilized mice harboring a deletion in the NR3C1 gene (GR dim ), which was reported to prevent GR transcriptional regulation through direct DNA-binding, and tissue-transplant techniques from GR-deficient mice [58, 59]. In the viable GR dim mice, mammary gland development was impaired due to reduced ductal epithelial cell proliferation in virgin mice, although mammary gland differentiation and milk production during pregnancy was normal [59].…”

“…The GR dim mutant maintains transcriptional regulation through protein:protein interactions, and direct transactivation by the GR dim mutant has been described for some genes, indicating that the mechanisms of GR action in the mammary gland remain poorly understood in this model [60]. Embryonic mammary buds from mice with a disrupted second exon of NR3C1 were transplanted into the cleared mammary fat pad of three-week-old recipient mice to circumvent perinatal lethality and study the role of GR in mammary gland development [52, 58]. These transplants displayed abnormal ductal morphogenesis in virgin mice but no defects in development during pregnancy, lactation, or involution.…”