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: 12.64). 10/2009; 23(20):2382-7. DOI: 10.1101/gad.1840109
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Yonatan Feuermann, Aug 22, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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; DOI:10.1530/ERC-14-0032 · 4.91 Impact Factor
  • Source
    • "During early pregnancy, STAT5 has also been shown to be essential for the generation and proliferation of alveolar progenitor cells from the mammary stem cell compartment (Gallego et al., 2001; Yamaji et al., 2009). Ablation of STAT5 prevents the development of immature alveoli at pregnancy day 6 (Yamaji et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, programed cell death and stromal reorganization to clear the differentiated milk-producing cells. Not surprisingly, the signaling pathways responsible for bringing about these changes in breast cells are often subverted during the process of tumorigenesis. The STAT family of proteins is involved in every stage of mammary gland development, and is also frequently implicated in breast tumorigenesis. While the roles of STAT3 and STAT5 during mammary gland development and tumorigenesis are well studied, others members, e.g. STAT1 and STAT6, have only recently been observed to play a role in mammary gland biology. Continued investigation into the STAT protein network in the mammary gland will likely yield new biomarkers and risk factors for breast cancer, and may also lead to novel prophylactic or therapeutic strategies against breast cancer.
    Molecular and Cellular Endocrinology 03/2013; 382(1). DOI:10.1016/j.mce.2013.03.014 · 4.24 Impact Factor
  • Source
    • "However, this up-regulation of Stat5 activation is not associated with a change in the level of Elf5 or the prolactin receptor (Supplemental Fig. S9c,d). Furthermore, expression of the milk protein gene WAP is considerably reduced in zfp157 lacZ/lacZ glands, suggesting that the pStat5-positive cells are undifferentiated luminal progenitors (Supplemental Fig. S9e; Yamaji et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lineage commitment studies in mammary glands have focused on identifying cell populations that display stem or progenitor properties. However, the mechanisms that control cell fate have been incompletely explored. Herein we show that zinc finger protein 157 (Zfp157) is required to establish the balance between luminal alveolar pStat5- and Gata-3-expressing cells in the murine mammary gland. Using mice in which the zfp157 gene was disrupted, we found that alveologenesis was accelerated concomitantly with a dramatic skewing of the proportion of pStat5-expressing cells relative to Gata-3⁺ cells. This suppression of the Gata-3⁺ lineage was associated with increased expression of the inhibitor of helix-loop-helix protein Id2. Surprisingly, Gata-3 becomes dispensable in the absence of Zfp157, as mice deficient for both Zfp157 and Gata-3 lactate normally, although the glands display a mild epithelial dysplasia. These data suggest that the luminal alveolar compartment of the mammary gland is comprised of a number of distinct cell populations that, although interdependant, exhibit considerable cell fate plasticity.
    Genes & development 05/2012; 26(10):1086-97. DOI:10.1101/gad.184051.111 · 12.64 Impact Factor
Show more