Glucocorticoid induced impairment of mammary gland involution is associated to STAT5 and STAT3 signaling modulation

PAOLA Y. BERTUCCI, ANA QUAGLINO, ANDREA G. POZZI, EDITH C. KORDON AND ADALI PECCI

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2010 vol. 151 p. 5730 - 5740

0013-7227

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 remodelling. 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 post-lactating 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 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 showed herein indicate that glucocorticoids are able to modulate early involution by controlling the strong crosstalk that GR, STAT5 and STAT3 pathways maintains in the mammary epithelium.