Abstract
Mammary gland regression following weaning (involution) is associated with extensive cell death and the acquisition of an inflammatory signature. Characterizing the interplay between mammary epithelial cells, the re-emerging stroma and immune cells has implications for the understanding of the pathogenesis of pregnancy-associated breast cancer. Stat3 has a role in orchestrating cell death and involution, and we sought to determine whether expression of Stat3 by the mammary epithelium also influences the innate immune environment and inflammatory cell influx in the gland. We examined mice in which Stat3 is conditionally deleted only in the mammary epithelium. Distinct sets of genes associated with the acute phase response and innate immunity are markedly up-regulated during first phase involution in a Stat3-dependent manner. During second phase involution, chitinase 3-like 1, which has been associated with wound healing and chronic inflammatory conditions, is dramatically up-regulated by Stat3. Also at this time, the number of mammary macrophages and mast cells increases per unit area, and this increase is impaired in the absence of epithelial Stat3. Furthermore, expression of arginase-1 and Ym1, markers of alternatively activated macrophages, is significantly decreased in the absence of Stat3, whilst iNOS, a marker associated with classically activated macrophages, shows significantly increased expression in the Stat3-deleted glands. Thus, Stat3 is a key transcriptional regulator of genes associated with innate immunity and wound healing and influences mammary macrophage and mast cell numbers. The presence of epithelial Stat3 appears to polarize the macrophages and epithelial cells towards an alternatively activated phenotype, since in the absence of Stat3, the gland retains a phenotype associated with classically activated macrophages. These findings have relevance to the study of pregnancy-associated breast cancer and the role of Stat3 signalling in recruitment of alternatively activated tumour-associated macrophages in breast cancer. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Highlights
Mammary gland involution comprises the retrograde change of the organ to its pre-pregnant state following weaning
This finding is notable, as it suggests that signal transducer and activator of transcription 3 (Stat3), expressed by the mammary epithelial cells themselves, is responsible for the acute phase response and regulation of the inflammatory environment of the gland during early involution
By 6 days of involution, levels of chitinase 3-like 1 (Chi3L1) are comparable between control and OSM and its receptor (OSMR) KO animals, pStat3 expression is negligible in the latter (Figure 2D). This is interesting, as it suggests that Stat3 is not the sole regulator of Chi3L1 expression in mammary gland involution
Summary
Mammary gland involution comprises the retrograde change of the organ to its pre-pregnant state following weaning. Mammary gland involution has reversible and irreversible phases. Stat has a pivotal role in mediating involution and mice with a mammary-specific conditional deletion of Stat exhibit a notable delay in this process [4,5]. Mammary Stat is expressed throughout a reproductive cycle, it is activated by tyrosine phosphorylation transiently on the day of birth and 6–12 h after weaning. The initial activator of Stat in the mammary gland is LIF [1,10] and during reversible involution Stat regulates lysosomalmediated programmed cell death in the mammary epithelial cells [6]. Stat is activated by OSM and its receptor (OSMR).
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