Abstract
The mammary epithelium undergoes cyclical periods of cellular proliferation, differentiation, and regression. During lactation, the signal transducer and activator of transcription factor (STAT)-5A and the glucocorticoid receptor (GR) synergize to induce milk protein expression and also act as survival factors. During involution, STAT3 activation mediates epithelial cell apoptosis and mammary gland remodeling. It has been shown that the administration of glucocorticoids at weaning prevents epithelial cell death, probably by extracellular matrix breakdown prevention. Our results show that the synthetic glucocorticoid dexamethasone (DEX) modulates STAT5A and STAT3 signaling and inhibits apoptosis induction in postlactating mouse mammary glands, only when administered within the first 48 h upon cessation of suckling. DEX administration right after weaning delayed STAT5A inactivation and degradation, preserving gene expression of target genes as β-casein (bcas) and prolactin induced protein (pip). Weaning-triggered GR down-regulation is also delayed by the hormone treatment. Moreover, DEX administration delayed STAT3 activation and translocation into epithelial cells nuclei. In particular, DEX treatment impaired the increment in gene expression of signal transducer subunit gp130, normally up-regulated from lactation to involution and responsible for STAT3 activation. Therefore, the data shown herein indicate that glucocorticoids are able to modulate early involution by controlling the strong cross talk that GR, STAT5, and STAT3 pathways maintains in the mammary epithelium.
Highlights
Mammary gland development is a complex and highly regulated multistep process
Is cross talk between glucocorticoid receptor (GR) and signal transducers and activators of transcription (STATs) families of transcription factors mediating the dramatic switch from survival to death signaling at weaning? Could the inhibition in mammary apoptosis generated by glucocorticoids be associated with modulation of STAT5 and STAT3 signaling pathways? The results presented in this study provide a novel insight into the molecular mechanisms modulating the switch between lactation and involution in mammary epithelial cells
Similar results were obtained with total STAT5A expression levels: the dramatic decrease observed in involuting glands was delayed by DEX treatment
Summary
Mammary gland development is a complex and highly regulated multistep process. First, from pregnancy to lactation, lobuloalveolar growth is followed by the complete differentiation of the mammary epithelium, which is involved in the production and secretion of milk proteins. Two families of inducible transcription factors have been found to play a key role in mediating different processes in mammary gland development and involution: the glucocorticoid receptor (GR), and the signal transducers and activators of transcription (STATs). It has been reported that different STAT family members interact physically and functionally with GR in several tissues and cell lines (6 –16) Cross talk between both families of transcription factors has been found in the regulation of cell proliferation, differentiation, and survival, in a tissuespecific manner. The circulating PRL leads to activation of its receptor, resulting in tyrosine phosphorylation of STAT5A and STAT5B by JAK2 [21] These two members of the STAT family share more than 90% of their sequence identity and usually play redundant functions [22]. PIP has been described as an antiapoptotic factor and has been designated as a sensitive and specific marker for monitoring and defining apocrine differentiation in breast cancer [30]
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