Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A

Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genes & development (Impact Factor: 10.8). 10/2009; 23(20):2382-7. DOI: 10.1101/gad.1840109
Source: PubMed


Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B, which mediate cytokine signaling. To reveal the underlying causes for this developmental block, we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and its ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Thus, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells.

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Available from: Yonatan Feuermann, Oct 02, 2015
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    • "The effect of pseudopregnancy (21 days of estrogen/progesterone pellet followed by 2 months involution) was sufficient to change the methylation status of luminal cells in a manner that is very similar to that of true pregnancy (Figure S3C). This is in agreement with the notion that luminal cells constitute the most abundant and most dynamic cell type in the mammary gland during pregnancy (Yamaji et al., 2009). "
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    ABSTRACT: Pregnancy is the major modulator of mammary gland activity. It induces a tremendous expansion of the mammary epithelium and the generation of alveolar structures for milk production. Anecdotal evidence from multiparous humans indicates that the mammary gland may react less strongly to the first pregnancy than it does to subsequent pregnancies. Here, we verify that the mouse mammary gland responds more robustly to a second pregnancy, indicating that the gland retains a long-term memory of pregnancy. A comparison of genome-wide profiles of DNA methylation in isolated mammary cell types reveals substantial and long-lasting alterations. Since these alterations are maintained in the absence of the signal that induced them, we term them epigenetic. The majority of alterations in DNA methylation affect sites occupied by the Stat5a transcription factor and mark specific genes that are upregulated during pregnancy. We postulate that the epigenetic memory of a first pregnancy primes the activation of gene expression networks that promote mammary gland function in subsequent reproductive cycles. More broadly, our data indicate that physiological experience can broadly alter epigenetic states, functionally modifying the capacity of the affected cells to respond to later stimulatory events. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 11(7). DOI:10.1016/j.celrep.2015.04.015 · 8.36 Impact Factor
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    • "NRG1 is a paracrine factor expressed in mammary myoepithelial cells required for normal ERBB4 and STAT5 activation in luminal mammary epithelium (Forster et al. 2014). STAT5 activation in mammary luminal progenitor cells is required for normal lobuloalveolar development (Liu et al. 1997, Cui et al. 2004, Yamaji et al. 2009). TRP63 also contributes to regulating involution. "
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    ABSTRACT: Trp63, founding member of the Trp53 family, contributes to epithelial differentiation and is expressed in breast neoplasia. Trp63 features two distinct promoters yielding specific mRNAs encoding two major TRP63 isoforms, a transactivating transcription factor and a dominant negative isoform. Specific TRP63 isoforms are linked to cell cycle arrest, apoptosis, survival and epithelial mesenchymal transition. Although TRP63 overexpression in cultured cells is used to elucidate functions, little is known about Trp63 regulation in normal and cancerous mammary tissue. This study used ChIP-seq to interrogate transcription factor binding and histone modifications of the Trp63 locus in mammary tissue and RNA-seq and immunohistochemistry to gauge gene expression. H3K4me2 and H3K4me3 marks coincided only with the proximal promoter, supporting RNA-seq data showing the predominance of the dominant negative isoform. STAT5 bound specifically to the Trp63 proximal promoter and Trp63 mRNA levels were elevated upon deleting STAT5 from mammary tissue, suggesting its role as a negative regulator. The dominant negative TRP63 isoform was localized to nuclei of basal mammary epithelial cells throughout reproductive cycles, and retained in a majority of the triple negative cancers generated from loss of full-length BRCA1. Increased expression of dominant negative isoforms was correlated with developmental windows of increased progesterone receptor binding to the proximal Trp63 promoter and decreased expression during lactation was correlated with STAT5 binding to the same region. TRP63 is present in the majority of triple negative cancers resulting from loss of BRCA1 but diminished in less differentiated cancer subtypes and in cancer cells undergoing epithelial mesenchymal transition.
    Endocrine Related Cancer 04/2014; 21(3). DOI:10.1530/ERC-14-0032 · 4.81 Impact Factor
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    • "In addition to the prolactin pathway, STAT5 can also be activated by epidermal growth factor (EGF), growth hormone, insulin growth factor (IGF), estrogen, and progesterone signaling pathways in the mammary gland [105]. STAT5 controls the population of luminal progenitor cells that will differentiate to alveolar cells [106,107]. During lactogenesis and lactation, the prolactin-STAT5 pathway controls the expression of milk protein genes and lipogenic genes [81,108]. "
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    ABSTRACT: Hypoxia is a physiological or pathological condition of a deficiency of oxygen supply in the body as a whole or within a tissue. During hypoxia, tissues undergo a series of physiological responses to defend themselves against a low oxygen supply, including increased angiogenesis, erythropoiesis, and glucose uptake. The effects of hypoxia are mainly mediated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimeric transcription factor consisting of alpha and beta subunits. HIF-1beta is constantly expressed, whereas HIF-1alpha is degraded under normal oxygen conditions. Hypoxia stabilizes HIF-1alpha and the HIF complex, and HIF then translocates into the nucleus to initiate the expression of target genes. Hypoxia has been extensively studied for its role in promoting tumor progression, and emerging evidence also indicates that hypoxia may play important roles in physiological processes, including mammary development and lactation. The mammary gland exhibits an increasing metabolic rate from pregnancy to lactation to support mammary growth, lactogenesis, and lactation. This process requires increasing amounts of oxygen consumption and results in localized chronic hypoxia as confirmed by the binding of the hypoxia marker pimonidazole HCl in mouse mammary gland. We hypothesized that this hypoxic condition promotes mammary development and lactation, a hypothesis that is supported by the following several lines of evidence: i) Mice with an HIF-1alpha deletion selective for the mammary gland have impaired mammary differentiation and lipid secretion, resulting in lactation failure and striking changes in milk compositions; ii) We recently observed that hypoxia significantly induces HIF-1alpha-dependent glucose uptake and GLUT1 expression in mammary epithelial cells, which may be responsible for the dramatic increases in glucose uptake and GLUT1 expression in the mammary gland during the transition period from late pregnancy to early lactation; and iii) Hypoxia and HIF-1alpha increase the phosphorylation of signal transducers and activators of transcription 5a (STAT5a) in mammary epithelial cells, whereas STAT5 phosphorylation plays important roles in the regulation of milk protein gene expression and mammary development. Based on these observations, hypoxia effects emerge as a new frontier for studying the regulation of mammary development and lactation.
    Journal of Animal Science and Biotechnology 01/2014; 5(1):9. DOI:10.1186/2049-1891-5-9 · 1.68 Impact Factor
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