The role of Stat3 in mammary gland involution: cell death regulator and modulator of inflammation

Abstract

AbstractMammary gland regression post-weaning (involution) is a highly regulated, complicated process in which the transcription factor Stat3 is a key player. Over the last decade, microarray analyses have had a profound impact on our understanding of this role. Studies using mammary epithelial cells in which Stat3 was activated in a ligand-independent manner have allowed direct transcriptional targets of Stat3 to be identified. Additionally, global gene expression changes during involution have been profiled by microarray analyses, which allowed characterization of clusters of genes with distinct expression profiles during the first 4 days of involution. Such expression profiling led to the observation that one of the most strikingly upregulated genes in the absence of Stat3 is the serpin Spi2a. This led to the discovery that mammary epithelial cell lysosomes undergo lysosomal membrane permeablisation and leak cathepsins during involution. Stat3 upregulates the expression of cathepsins B and L within 24 h of weaning and is thus the critical inducer of lysosomal-mediated cell death during this process. In addition to its pivotal role in the control of cell death during involution, microarray-based studies have demonstrated that the expression of acute phase and inflammatory genes is regulated by Stat3 and that mammary epithelial expression of this transcription factor modulates the phenotype of macrophages present in the gland during second phase remodelling. Thus, Stat3 signalling may have effects that are not cell-autonomous, in addition to its cell-autonomous role in involution.