scholarly journals Epithelial Xbp1 Is Required for Cellular Proliferation and Differentiation during Mammary Gland Development

2015 ◽  
Vol 35 (9) ◽  
pp. 1543-1556 ◽  
Author(s):  
Daisuke Hasegawa ◽  
Veronica Calvo ◽  
Alvaro Avivar-Valderas ◽  
Abigale Lade ◽  
Hsin-I Chou ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Cellular Proliferation ◽  
Prolactin Receptor ◽  
Mammary Epithelium ◽  
Branching Morphogenesis ◽  
Direct Function ◽  
Proliferation And Differentiation ◽  
The Unfolded Protein Response ◽  
Gland Development

Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1α-mediated splicing, which results in a frameshift to encode a protein with transcriptional activity. However, the direct function of Xbp1 in epithelial cells during mammary gland development is unknown. Here we report that the loss of Xbp1 in the mammary epithelium through targeted deletion leads to poor branching morphogenesis, impaired terminal end bud formation, and spontaneous stromal fibrosis during the adult virgin period. Additionally, epithelial Xbp1 deletion induces endoplasmic reticulum (ER) stress in the epithelium and dramatically inhibits epithelial proliferation and differentiation during lactation. The synthesis of milk and its major components, α/β-casein and whey acidic protein (WAP), is significantly reduced due to decreased prolactin receptor (Prlr) and ErbB4 expression in Xbp1-deficient mammary epithelium. Reduction of Prlr and ErbB4 expression and their diminished availability at the cell surface lead to reduced phosphorylated Stat5, an essential regulator of cell proliferation and differentiation during lactation. As a result, lactating mammary glands in these mice produce less milk protein, leading to poor pup growth and postnatal death. These findings suggest that the loss of Xbp1 induces a terminal UPR which blocks proliferation and differentiation during mammary gland development.

scholarly journals Regulation of Mammary Gland Branching Morphogenesis by EphA2 Receptor Tyrosine Kinase

2009 ◽  
Vol 20 (10) ◽  
pp. 2572-2581 ◽  
Author(s):  
David Vaught ◽  
Jin Chen ◽  
Dana M. Brantley-Sieders
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Mammary Epithelium ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Mammary Tissue ◽  
Wild Type ◽  
Epithelial Proliferation ◽  
Positive Role ◽  
Gland Development

Eph receptor tyrosine kinases, including EphA2, are expressed in the mammary gland. However, their role in mammary gland development remains poorly understood. Using EphA2-deficient animals, we demonstrate for the first time that EphA2 receptor function is required for mammary epithelial growth and branching morphogenesis. Loss of EphA2 decreased penetration of mammary epithelium into fat pad, reduced epithelial proliferation, and inhibited epithelial branching. These defects appear to be intrinsic to loss of EphA2 in epithelium, as transplantation of EphA2-deficient mammary tissue into wild-type recipient stroma recapitulated these defects. In addition, HGF-induced mammary epithelial branching morphogenesis was significantly reduced in EphA2-deficient cells relative to wild-type cells, which correlated with elevated basal RhoA activity. Moreover, inhibition of ROCK kinase activity in EphA2-deficient mammary epithelium rescued branching defects in primary three-dimensional cultures. These results suggest that EphA2 receptor acts as a positive regulator in mammary gland development, functioning downstream of HGF to regulate branching through inhibition of RhoA. Together, these data demonstrate a positive role for EphA2 during normal mammary epithelial proliferation and branching morphogenesis.

Targeting heparanase to the mammary epithelium enhances mammary gland development and promotes tumor growth and metastasis

2018 ◽  
Vol 65 ◽  
pp. 91-103 ◽  
Author(s):  
Ilanit Boyango ◽  
Uri Barash ◽  
Liat Fux ◽  
Inna Naroditsky ◽  
Neta Ilan ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Tumor Growth ◽  
Mammary Gland Development ◽  
Mammary Epithelium ◽  
Tumor Growth And Metastasis ◽  
Gland Development

Foxp3 heterozygosity does not overtly affect mammary gland development during puberty or the oestrous cycle in mice

2020 ◽  
Vol 32 (8) ◽  
pp. 774
Author(s):  
Vahid Atashgaran ◽  
Pallave Dasari ◽  
Leigh J. Hodson ◽  
Andreas Evdokiou ◽  
Simon C. Barry ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
Cancer Susceptibility ◽  
Branching Morphogenesis ◽  
Genetic Mutation ◽  
Oestrous Cycle ◽  
Normal Mammary Gland ◽  
Foxp3 Mrna ◽  
Gland Development

Female mice heterozygous for a genetic mutation in transcription factor forkhead box p3 (Foxp3) spontaneously develop mammary cancers; however, the underlying mechanism is not well understood. We hypothesised that increased cancer susceptibility is associated with an underlying perturbation in mammary gland development. The role of Foxp3 in mammary ductal morphogenesis was investigated in heterozygous Foxp3Sf/+ and wildtype Foxp3+/+ mice during puberty and at specific stages of the oestrous cycle. No differences in mammary ductal branching morphogenesis, terminal end bud formation or ductal elongation were observed in pubertal Foxp3Sf/+ mice compared with Foxp3+/+ mice. During adulthood, all mice underwent normal regular oestrous cycles. No differences in epithelial branching morphology were detected in mammary glands from mice at the oestrus, metoestrus, dioestrus and pro-oestrus stages of the cycle. Furthermore, abundance of Foxp3 mRNA and protein in the mammary gland and lymph nodes was not altered in Foxp3Sf/+ mice compared with Foxp3+/+ mice. These studies suggest that Foxp3 heterozygosity does not overtly affect mammary gland development during puberty or the oestrous cycle. Further studies are required to dissect the underlying mechanisms of increased mammary cancer susceptibility in Foxp3Sf/+ heterozygous mice and the function of this transcription factor in normal mammary gland development.

scholarly journals The Role of microRNAs in the Mammary Gland Development, Health, and Function of Cattle, Goats, and Sheep

2021 ◽  
Vol 7 (4) ◽  
pp. 78
Author(s):  
Artem P. Dysin ◽  
Olga Y. Barkova ◽  
Marina V. Pozovnikova
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Cellular Proliferation ◽  
Climatic Conditions ◽  
Structural Element ◽  
Small Noncoding Rnas ◽  
Current State ◽  
Complex Structural ◽  
And Function ◽  
Gland Development

Milk is an integral and therefore complex structural element of mammalian nutrition. Therefore, it is simple to conclude that lactation, the process of producing milk, is as complex as the mammary gland, the organ responsible for this biochemical activity. Nutrition, genetics, epigenetics, disease pathogens, climatic conditions, and other environmental variables all impact breast productivity. In the last decade, the number of studies devoted to epigenetics has increased dramatically. Reports are increasingly describing the direct participation of microRNAs (miRNAs), small noncoding RNAs that regulate gene expression post-transcriptionally, in the regulation of mammary gland development and function. This paper presents a summary of the current state of knowledge about the roles of miRNAs in mammary gland development, health, and functions, particularly during lactation. The significance of miRNAs in signaling pathways, cellular proliferation, and the lipid metabolism in agricultural ruminants, which are crucial in light of their role in the nutrition of humans as consumers of dairy products, is discussed.

scholarly journals DC-SCRIPT deficiency delays mouse mammary gland development and branching morphogenesis

2019 ◽  
Vol 455 (1) ◽  
pp. 42-50
Author(s):  
Chunling Tang ◽  
Renske J.E. van den Bijgaart ◽  
Maaike W.G. Looman ◽  
Nina Tel-Karthaus ◽  
Annemarie M.A. de Graaf ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Branching Morphogenesis ◽  
Mouse Mammary Gland ◽  
Gland Development

scholarly journals Chemokine receptors ACKR2 and CCR1 coordinate macrophage dynamics and mammary gland development

2019 ◽  
Author(s):  
Gillian J Wilson ◽  
Ayumi Fukuoka ◽  
Samantha R Love ◽  
Jiwon Kim ◽  
Marieke Pingen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Mammary Gland Development ◽  
Branching Morphogenesis ◽  
Unknown Mechanism ◽  
Key Population ◽  
Ductal Elongation ◽  
Gland Development

AbstractMacrophages are key regulators of developmental processes, including those involved in mammary gland development. We previously demonstrated that the atypical chemokine receptor, ACKR2, contributes to control of ductal epithelial branching in the developing mammary gland by regulating macrophage dynamics. ACKR2 is a chemokine-scavenging receptor, which mediates its effects through collaboration with inflammatory chemokine receptors (iCCRs). Here we reveal that ACKR2, and the iCCR CCR1, reciprocally regulate branching morphogenesis in the mammary gland, whereby stromal ACKR2 modulates levels of the shared ligand CCL7 to control the movement of a key population of CCR1-expressing macrophages to the ductal epithelium. In addition estrogen, which is essential for ductal elongation during puberty, upregulates CCR1 expression on macrophages. The age at which girls develop breasts is decreasing, which raises the risk of diseases including breast cancer. This study presents a previously unknown mechanism controlling the rate of mammary gland development during puberty and highlights potential therapeutic targets.SummaryIn the mammary gland during puberty, availability of the chemokine CCL7 is controlled by a scavenging receptor ACKR2 and provides a key signal to macrophages which have the receptor CCR1. Together, this controls the timing of development.

scholarly journals Primary mammary organoid model of lactation and involution

2019 ◽  
Author(s):  
Jakub Sumbal ◽  
Aurelie Chiche ◽  
Elsa Charifou ◽  
Zuzana Koledova ◽  
Han Li
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Developmental Stages ◽  
System Modeling ◽  
Three Dimensional ◽  
Mammary Epithelium ◽  
Branching Morphogenesis ◽  
Pregnancy And Lactation ◽  
Key Aspects ◽  
Gland Development

AbstractMammary gland development occurs mainly after birth and is composed of three successive stages: puberty, pregnancy and lactation, and involution. These developmental stages are associated with major tissue remodeling, including extensive changes in mammary epithelium as well as surrounding stroma. Three-dimensional (3D) mammary organoid culture has become an important tool in mammary gland biology and enabled invaluable discoveries on pubertal mammary branching morphogenesis and breast cancer. However, a suitable 3D organoid model recapitulating key aspects of lactation and involution has been missing. Here, we describe a robust and straightforward mouse mammary organoid system modeling lactation and involution-like process, which can be applied to study mechanisms of physiological mammary gland lactation and involution as well as pregnancy-associated breast cancer.

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