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Nucleic Acids Research Feb 2016Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most...
Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development and function. We report that the ubiquitously expressed Stat5a/b locus is subject to additional lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitivity, H3K27 acetylation and binding by GR, NFIB, ELF5 and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that contributes to the remarkable abundance of STAT5 and, in turn, to the efficacy of STAT5-dependent mammary physiology.
Topics: Animals; Base Sequence; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Enhancer Elements, Genetic; Female; Humans; Mammary Glands, Human; Mice; Molecular Sequence Data; STAT5 Transcription Factor
PubMed: 26446995
DOI: 10.1093/nar/gkv999 -
Journal of Mammary Gland Biology and... Jun 2015The mammary epithelium is a highly heterogenous and dynamic tissue that includes a range of cell types with varying levels of proliferative capacity and differentiation... (Review)
Review
The mammary epithelium is a highly heterogenous and dynamic tissue that includes a range of cell types with varying levels of proliferative capacity and differentiation potential, from stem to committed progenitor and mature cells. Generation of mature cells through expansion and specification of immature precursors is driven by hormonal and local stimuli. Intriguingly, although circulating hormones can be directly sensed only by a subset of mammary cells, they also regulate the behaviour of cells lacking their cognate receptors through paracrine mechanisms. Thus, mapping the hormonal signalling network on to the emerging mammary cell hierarchy appears to be a difficult task. Nevertheless, a first step towards a better understanding is the characterization of the hormone receptor expression pattern across individual cell types in the mammary epithelium. Here we review the most relevant findings on the cellular distribution of hormone receptors in the mammary gland, taking into account differences between mice and humans, the methods employed to assess receptor expression as well as the variety of approaches used to resolve the mammary cell heterogeneity.
Topics: Animals; Cell Differentiation; Cell Lineage; Cell Proliferation; Epithelium; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Stem Cells
PubMed: 26193872
DOI: 10.1007/s10911-015-9336-1 -
Cell Reports Jul 2019DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but...
DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but also promote tissue aging. Because mice lacking Slug/Snai2 exhibit limited stem cell activity, including luminobasal differentiation, and are protected from mammary cancer, we reasoned that Slug might regulate DNA damage checkpoints in mammary epithelial cells. Here, we show that Slug facilitates efficient execution of RPA32-mediated DNA damage response (DDR) signaling. Slug deficiency leads to delayed phosphorylation of ataxia telangiectasia mutated and Rad3-related protein (ATR) and its effectors RPA32 and CHK1. This leads to impaired RAD51 recruitment to DNA damage sites and persistence of unresolved DNA damage. In vivo, Slug/Snai2 loss leads to increased DNA damage and premature aging of mammary epithelium. Collectively, our work demonstrates that the mammary stem cell regulator Slug controls DDR checkpoints by dually inhibiting differentiation and facilitating DDR repair, and its loss causes unresolved DNA damage and accelerated aging.
Topics: Animals; Cell Differentiation; Cell Line; Cell Line, Tumor; Cellular Senescence; DNA Damage; DNA Repair; HEK293 Cells; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mice; Mice, Inbred NOD; Mice, SCID; Snail Family Transcription Factors
PubMed: 31291576
DOI: 10.1016/j.celrep.2019.06.043 -
Viruses Oct 2019Zika virus (ZIKV) belongs to the large category of arboviruses. Surprisingly, several human-to-human transmissions of ZIKV have been notified, either following sexual...
Zika virus (ZIKV) belongs to the large category of arboviruses. Surprisingly, several human-to-human transmissions of ZIKV have been notified, either following sexual intercourse or from the mother to fetus during pregnancy. Importantly, high viral loads have been detected in the human breast milk of infected mothers, and the existence of breastfeeding as a new mode of mother-to-child transmission of ZIKV was recently hypothesized. However, the maternal origin of infectious particles in breast milk is currently unknown. Here, we show that ZIKV disseminates to the mammary glands of infected mice after both systemic and local exposure with differential kinetics. Ex vivo, we demonstrate that primary human mammary epithelial cells were sensitive and permissive to ZIKV infection in this study. Moreover, by using in vitro models, we prove that mammary luminal- and myoepithelial-phenotype cell lines are both able to produce important virus progeny after ZIKV exposure. Our data suggest that the dissemination of ZIKV to the mammary glands and subsequent infection of the mammary epithelium could be one mechanism of viral excretion in human breast milk.
Topics: Animals; Cell Line; Epithelial Cells; Female; Humans; Infectious Disease Transmission, Vertical; Mammary Glands, Human; Mice; Milk, Human; Pregnancy; RNA, Viral; Viral Load; Viral Tropism; Virus Replication; Zika Virus
PubMed: 31619008
DOI: 10.3390/v11100950 -
Disease Models & Mechanisms Mar 2022RET is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors with oncogenic activity in the breast are known to participate in...
RET is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors with oncogenic activity in the breast are known to participate in specific developmental stages. We found that RET is differentially expressed during mouse mammary gland development: RET is present in lactation and its expression dramatically decreases in involution, the period during which the lactating gland returns to a quiescent state after weaning. Based on epidemiological and pre-clinical findings, involution has been described as tumor promoting. Using the Ret/MTB doxycycline-inducible mouse transgenic system, we show that sustained expression of RET in the mammary epithelium during the post-lactation transition to involution is accompanied by alterations in tissue remodeling and an enhancement of cancer potential. Following constitutive Ret expression, we observed a significant increase in neoplastic lesions in the post-involuting versus the virgin mammary gland. Furthermore, we show that abnormal RET overexpression during lactation promotes factors that prime involution, including premature activation of Stat3 signaling and, using RNA sequencing, an acute-phase inflammatory signature. Our results demonstrate that RET overexpression negatively affects the normal post-lactation transition.
Topics: Animals; Female; Humans; Lactation; Mammary Glands, Animal; Mammary Glands, Human; Mice; Neoplasms; Proto-Oncogene Proteins c-ret; STAT3 Transcription Factor
PubMed: 35044452
DOI: 10.1242/dmm.049286 -
Molecular and Cellular Endocrinology Jun 2012This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies... (Review)
Review
This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor activator of nuclear factor κB ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression.
Topics: Animals; Breast Neoplasms; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mice; Pregnancy; Progesterone; Progestins; RANK Ligand; Receptors, Progesterone; Signal Transduction
PubMed: 22193050
DOI: 10.1016/j.mce.2011.10.030 -
Journal of Mammary Gland Biology and... Jun 2008The ErbB receptor tyrosine kinase family has often been associated with increased growth of breast epithelial cells, as well as malignant transformation and progression.... (Review)
Review
The ErbB receptor tyrosine kinase family has often been associated with increased growth of breast epithelial cells, as well as malignant transformation and progression. In contrast, ErbB4/HER4 exhibits unique attributes from a two step proteolytic cleavage which releases an 80 kilodalton, nuclear localizing, tyrosine kinase to a signal transduction mechanism that slows growth and stimulates differentiation of breast cells. This review provides an overview of ErbB4/HER4 in growth and differentiation of the mammary epithelium, including its physiologic role in development, the contrasting growth inhibition/tumor suppression and growth acceleration of distinct ErbB4/HER4 isoforms and a description of the unique cell cycle regulated pattern of nuclear HER4 ubiquitination and destruction.
Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Cell Differentiation; ErbB Receptors; Female; Growth Inhibitors; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mice; Protein Isoforms; Receptor, ErbB-4; Signal Transduction; Tumor Cells, Cultured
PubMed: 18437540
DOI: 10.1007/s10911-008-9080-x -
Laboratory Investigation; a Journal of... Mar 2012The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many... (Review)
Review
The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many different biological processes, including cell proliferation, cell differentiation, embryonic development, neoplasia, hematopoiesis, angiogenesis, and inflammation. The epithelium-specific ETS transcription factor-1 (ESE-1) is a physiologically important ETS transcription factor, which has been shown to play a role in the pathogenesis of various diseases, and was originally characterized as having an epithelial-restricted expression pattern, thus placing it within the epithelium-specific ETS subfamily. Despite a large body of published work on ETS biology, much remains to be learned about the precise functions of ESE-1 and other epithelium-specific ETS factors in regulating diverse disease processes. Clues as to the specific function of ESE-1 in the setting of various diseases can be obtained from studies aimed at examining the expression of putative target genes regulated by ESE-1. Thus, this review will focus primarily on the various roles of ESE-1 in different pathophysiological processes, including regulation of epithelial cell differentiation during both intestinal development and lung regeneration; regulation of dendritic cell-driven T-cell differentiation during allergic airway inflammation; regulation of mammary gland development and breast cancer; and regulation of the effects of inflammatory stimuli within the setting of synovial joint and vascular inflammation. Understanding the exact mechanisms by which ESE-1 regulates these processes can have important implications for the treatment of a wide range of diseases.
Topics: Adenocarcinoma; Animals; Breast Neoplasms; Carcinoma, Large Cell; Cell Differentiation; DNA-Binding Proteins; Embryonic Development; Epithelium; Female; Humans; Intestines; Lung; Lung Neoplasms; Mammary Glands, Human; Mice; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; Regeneration; Transcription Factors
PubMed: 22157719
DOI: 10.1038/labinvest.2011.186 -
Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis.Communications Biology Jun 2021The female mammary epithelium undergoes reorganization during development, pregnancy, and menopause, linking higher risk with breast cancer development. To characterize...
The female mammary epithelium undergoes reorganization during development, pregnancy, and menopause, linking higher risk with breast cancer development. To characterize these periods of complex remodeling, here we report integrated 50 K mouse and 24 K human mammary epithelial cell atlases obtained by single-cell RNA sequencing, which covers most lifetime stages. Our results indicate a putative trajectory that originates from embryonic mammary stem cells which differentiates into three epithelial lineages (basal, luminal hormone-sensing, and luminal alveolar), presumably arising from unipotent progenitors in postnatal glands. The lineage-specific genes infer cells of origin of breast cancer using The Cancer Genome Atlas data and single-cell RNA sequencing of human breast cancer, as well as the association of gland reorganization to different breast cancer subtypes. This comprehensive mammary cell gene expression atlas ( https://mouse-mammary-epithelium-integrated.cells.ucsc.edu ) presents insights into the impact of the internal and external stimuli on the mammary epithelium at an advanced resolution.
Topics: Animals; Breast; Breast Neoplasms; Carcinogenesis; Cell Lineage; Cell Transformation, Neoplastic; Databases, Nucleic Acid; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Humans; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Pregnancy; RNA-Seq
PubMed: 34079055
DOI: 10.1038/s42003-021-02201-2 -
Reproductive Toxicology (Elmsford, N.Y.) Jul 2015Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the genital tract and predisposed individuals to develop clear cell carcinoma of the... (Review)
Review
Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the genital tract and predisposed individuals to develop clear cell carcinoma of the vagina as well as breast cancer later in life. Gestational exposure of rodents to a related compound, the xenoestrogen bisphenol-A (BPA) increases the propensity to develop mammary cancer during adulthood, long after cessation of exposure. Exposure to BPA during gestation induces morphological alterations in both the stroma and the epithelium of the fetal mammary gland at 18 days of age. We postulate that the primary target of BPA is the fetal stroma, the only mammary tissue expressing estrogen receptors during fetal life. BPA would then alter the reciprocal stroma-epithelial interactions that mediate mammogenesis. In addition to this direct effect on the mammary gland, BPA is postulated to affect the hypothalamus and thus in turn affect the regulation of mammotropic hormones at puberty and beyond.
Topics: Age Factors; Animals; Benzhydryl Compounds; Breast Neoplasms; Cell Communication; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Endocrine Disruptors; Epithelial Cells; Estrogens; Female; Gestational Age; Humans; Hypothalamus; Mammary Glands, Animal; Mammary Glands, Human; Maternal Exposure; Phenols; Pregnancy; Prenatal Exposure Delayed Effects; Risk Assessment; Risk Factors; Stromal Cells
PubMed: 25277313
DOI: 10.1016/j.reprotox.2014.09.012