Novel role of microRNA146b in promoting mammary alveolar progenitor cell maintenance

Abstract

SummaryIn this report, we have shown that miR146b promotes the maintenance of pregnancy-derived mammary luminal alveolar progenitors. MiR146b expression was significantly higher in the mammary glands of pregnant and lactating mice than in virgin mice. Furthermore, miR146b levels were significantly higher in mouse mammary glands exposed to the sex hormones, estrogen and progesterone, compared with those of untreated control animals. Pregnancy-derived primary mouse mammary epithelial cells in which miR146b was knocked down showed a significant reduction in the number of hollow acinar organoid structures formed on three-dimensional Matrigel and in bcasein expression. This demonstrates that miR146b promotes the maintenance of pregnancy-derived mammary luminal alveolar progenitors. It has been shown that mouse mammary luminal progenitors give rise to hollow organoid structures, whereas solid organoid structures are derived from stem cells. Among several miR146b targets, miR146b knockdown resulted in preferential STAT3b overexpression. In the primary mouse mammary epithelial cells, overexpression of STAT3b isoform caused mammary epithelial cell death and a significant reduction in b-casein mRNA expression. Therefore, we conclude that during pregnancy miR146b is involved in luminal alveolar progenitor cell maintenance, at least partially, by regulating STAT3b.

Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer

“…It could relate to a general increase in the expression and function of the spliceosome machinery components in these cancer cells [ 49 ] or to alteration in a specific regulatory mechanism(s) normally controlling differential isoform generation. Recently miR146b has been reported to specifically degrade Stat3β in normal mammary luminal cells [ 50 ], suggesting this as a normal mode of regulation. Could the loss of this miRNA in breast cancer cells lead to an aberrant increase in Stat3β in these cells?…”

MiR‐146b attenuates high‐fat diet‐induced non‐alcoholic steatohepatitis in mice

“…Moreover, miR‐146b is downregulated in monocytes in obese patients, and miR‐146b is a regulator of the anti‐inflammatory, globular adiponectin . miR‐146b also play a role in senescence, mammary alveolar progenitor cell maintenance, erythropoiesis and megakaryocytopoiesis, glioma cell migration and invasion, and myoblast differentiation …”

“…12,13 Moreover, miR-146b is downregulated in monocytes in obese patients, and miR-146b is a regulator of the anti-inflammatory, globular adiponectin. 14 miR-146b also play a role in senescence, 15 mammary alveolar progenitor cell maintenance, 16 erythropoiesis and megakaryocytopoiesis, 17 glioma cell migration and invasion, 18 and myoblast differentiation. 19 Figure 1 miR-146b directly downregulates interleukin (IL)-1 receptor-associated kinase (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in macrophages after lipopolysaccharide (LPS) administration in vitro.…”

The STAT5-regulated miR-193b locus restrains mammary stem and progenitor cell activity and alveolar differentiation

“…The loci encoding miR-193b , miR-146b and miR-148a fulfilled the defining criteria, i.e., binding of STAT5 and PR to putative regulatory sequences, the presence of H3K4me3 and H3K4me2 marks and STAT5-dependent transcription (Figure 1A). While the miR-146a locus is also a bona fide STAT3 target in breast cancer cells (Xiang et al, 2014) and miR-146b controls mammary cell differentiation in vitro (Elsarraj et al, 2013), no pertinent information exists on the roles of the miR-148a and miR-193b loci in mammary development. MiR-193b is unique in that it is expressed significantly only in a few cell types, mammary epithelium, brown adipose tissue (Feuermann et al, 2013; Sun et al, 2011) and hematopoietic progenitor cells (Kuchen et al, 2010).…”

“…Studies with primary cells have demonstrated that miR-146b , a known STAT3 target (Xiang et al, 2014), promotes alveolar progenitor cells in a cell line-based organ culture system (Elsarraj et al, 2013). STAT5 and PR are also binding to respective regulatory sequences in this locus further supporting the notion that miR-146b executes hormone function in mammary epithelium.…”