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.

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.

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

scholarly journals p19ARFDetermines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development

2004 ◽  
Vol 15 (5) ◽  
pp. 2302-2311 ◽  
Author(s):  
Yijun Yi ◽  
Anne Shepard ◽  
Frances Kittrell ◽  
Biserka Mulac-Jericevic ◽  
Daniel Medina ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Protein Level ◽  
Normal Cell ◽  
Mammary Gland Development ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Proliferation Rate ◽  
Gland Development

This study demonstrated, for the first time, the following events related to p19ARFinvolvement in mammary gland development: 1) Progesterone appears to regulate p19ARFin normal mammary gland during pregnancy. 2) p19ARFexpression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19ARFprotein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19ARFin mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21Cip1and decrease in apoptosis, and 2) p19ARFnull cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21Cip1compared with WT cells. Although, p19ARFis dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19ARFnull mice, the upregulation of p19ARFby progesterone in the WT cells and the weakness of p21Cip1in mammary epithelial cells lacking p19ARFstrongly suggest that the functional role(s) of p19ARFin mammary gland development is critical to sustain normal cell proliferation rate during pregnancy and normal apoptosis in involution possibly through the p53-dependent pathway.

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 Expression and localisation of oestrogen and progesterone receptors in the bovine mammary gland during development, function and involution

2003 ◽  
Vol 177 (2) ◽  
pp. 305-317 ◽  
Author(s):  
D Schams ◽  
S Kohlenberg ◽  
W Amselgruber ◽  
B Berisha ◽  
MW Pfaffl ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mrna Expression ◽  
Western Blotting ◽  
Mammary Gland Development ◽  
Mammary Tissue ◽  
Positive Staining ◽  
Bovine Mammary Gland ◽  
Total Rna ◽  
Gland Development

It is now well established that oestrogen and progesterone are absolutely essential for mammary gland development. Lactation can be induced in non-pregnant animals by sex steroid hormone treatment. Most of the genomic actions of oestrogens are mediated by two oestrogen receptors (ER)-alpha and ERbeta, and for gestagens in ruminants by the progesterone receptor (PR). Our aim was the evaluation of mRNA expression and protein (localisation and Western blotting) during mammogenesis, lactogenesis, galactopoiesis (early, middle and late) and involution (8, 24, 28, 96-108 h and 14-28 days after the end of milking) in the bovine mammary gland (total no. 53). During these stages, the mRNA was assessed by means of real-time RT-PCR (LightCycler). The protein for ERalpha, ERbeta and PR was localised by immunohistochemistry and Western blotting. The mRNA expression results indicated the existence of ERalpha, ERbeta and PR in bovine mammary gland. Both ERalpha and PR are expressed in fg/ micro g total RNA range. The highest mRNA expression was found for ERalpha and PR in the tIssue of non-pregnant heifers, followed by a significant decrease to a lower level at the time of lactogenesis with low concentrations remaining during lactation and the first 4 weeks of involution. In contrast, the expression of ERbeta was about 1000-fold lower (ag/ micro g total RNA) and showed no clear difference during the stages examined, with a significant increase only 2-4 weeks after the end of milking. Immunolocalisation for ERalpha revealed a strong positive staining in nuclei of lactocytes in non-pregnant heifers, became undetectable during pregnancy, lactogenesis and lactation, and was again detectable 14-28 days after the end of milking. In contrast, PR was localised in the nuclei of epithelial cells in the mammary tIssue of non-pregnant heifers, in primigravid animals, and during late lactation and involution. During lactogenesis, peak and mid lactation, fewer nuclei of epithelial cells were positive, but increased staining of the cytoplasm of epithelial cells was obvious. ERalpha and ERbeta protein was found in all mammary gland stages examined by Western blotting. In contrast to mRNA expression, the protein signal for ERalpha was weaker in the tIssue of non-pregnant heifers and during involution (4 weeks). ERbeta protein showed a stronger signal (two isoform bands) in non-pregnant heifers and 4 weeks after the end of milking. This correlated with the mRNA expression data. Three isoforms of PR (A, B and C) were found by Western blotting in the tIssue of non-pregnant heifers, but only isoform B remained during the following stages (lactogenesis, galactopoiesis and involution). In conclusion, the mRNA expression and protein data for ER and PR showed clear regulatory changes, suggesting involvement of these receptors in bovine mammary gland development and involution.

scholarly journals Plasticity and Potency of Mammary Stem Cell Subsets During Mammary Gland Development

2019 ◽  
Vol 20 (9) ◽  
pp. 2357 ◽  
Author(s):  
Eunmi Lee ◽  
Raziye Piranlioglu ◽  
Max S. Wicha ◽  
Hasan Korkaya
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
Mammary Epithelial ◽  
Stem Cell Markers ◽  
Quiescent State ◽  
Mammary Stem Cells ◽  
Mammary Stem ◽  
Gland Development

It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, in which the mammary stem cells (MaSC) lie at the apex with regenerative capacity as well as plasticity. Despite the fact that the majority of studies supported the existence of multipotent MaSCs giving rise to both basal and luminal lineages, others proposed lineage restricted unipotent MaSCs. Consistent with the notion, the latest research has suggested that although normal MaSC subsets mainly stay in a quiescent state, they differ in their reconstituting ability, spatial localization, and molecular and epigenetic signatures in response to physiological stimuli within the respective microenvironment during the stages of mammary gland development. In this review, we will focus on current research on the biology of normal mammary stem cells with an emphasis on properties of cellular plasticity, self-renewal and quiescence, as well as the role of the microenvironment in regulating these processes. This will include a discussion of normal breast stem cell heterogeneity, stem cell markers, and lineage tracing studies.

scholarly journals Signal Transducer and Activator of Transcription 5a Mediates Mammary Ductal Branching and Proliferation in the Nulliparous Mouse

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2876-2885 ◽  
Author(s):  
Sarah J. Santos ◽  
Sandra Z. Haslam ◽  
Susan E. Conrad
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Gland Development ◽  
Kinase Inhibitor ◽  
Mammary Epithelial Cells ◽  
Nuclear Factor Κb ◽  
Mammary Glands ◽  
Mammary Epithelial ◽  
Signal Transducer ◽  
Gland Development

Signal transducer and activator of transcription (Stat)5a is a critical regulator of mammary gland development. Previous studies have focused on Stat5a’s role in the late pregnant and lactating gland, and although active Stat5a is detectable in mammary epithelial cells in virgin mice, little is known about its role during early mammary gland development. In this report, we compare mammary gland morphology in pubertal and adult nulliparous wild-type and Stat5a−/− mice. The Stat5a-null mammary glands exhibited defects in secondary and side branching, providing evidence that Stat5a regulates these processes. In addition, Stat5a−/− mammary glands displayed an attenuated proliferative response to pregnancy levels of estrogen plus progesterone (E+P), suggesting that it plays an important role in early pregnancy. Finally, we examined one potential mediator of Stat5a’s effects, receptor activator of nuclear factor-κB ligand (RANKL). Stat5a−/− mammary glands were defective in inducing RANKL in response to E+P treatment. In addition, regulation of several reported RANKL targets, including inhibitor of DNA binding 2 (Id2), cyclin D1, and the cyclin-dependent kinase inhibitor p21Waf1/Cip1, was altered in Stat5a−/− mammary cells, suggesting that one or more of these proteins mediate the effects of Stat5a in E+P-treated mammary epithelial cells.

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

Mammary Epithelial Cell Transcriptome Reveals Potential Roles of lncRNAs in Regulating Milk Synthesis Pathways in Jersey and Kashmiri Cattle

2021 ◽  
Author(s):  
Peerzada Tajamul Mumtaz ◽  
Basharat Bhat ◽  
Eveline M. Ibeagha-Awemu ◽  
Qamar Taban ◽  
Mengqi Wang ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Expression Profiles ◽  
Regulatory Elements ◽  
Milk Quality ◽  
Mammary Epithelial ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Gland Development

Abstract Background Long noncoding RNAs (lncRNAs) are now proven as essential regulatory elements, playing diverse role in many biological processes including mammary gland development. However, little is known about their roles in bovine lactation process. There are very few reports available to date on the role of lncRNAs in lactation physiology and mammary glands development in cattle. Results To identify and characterize the roles of lncRNAs in bovine lactation, milk derived mammary epithelial cells (MEC) from Jersey (high milk producer) and Kashmiri cattle (low milk producer) at early, mid and late lactation stages were used. The lncRNA transcriptome of the samples (n=18) was studied using next generation RNA sequencing technology. 633 putative lncRNAs were identified, 76 of which were differentially expressed (DE) between comparison between the three stages of lactation. Additionally, 56 DE lncRNAs were identified from 9 Jersey and 9 Kashmir samples. Correlation of DE lncRNAs with protein-coding genes resulted in a comprehensive list of lncRNA-mRNA co-expressed pairs. Most of the DE lncRNAs showed positive correlations with protein coding genes in Jersey compared to Kashmiri cattle where they were mainly negatively correlated, which could be one of the underlying mechanisms responsible for the differential milking performance between the two breeds. In addition, a number of the DE lncRNAs were paired with the most DE milk quality genes like GPAM, LPL, ABCG2, etc. indicative of their potential regulatory effects on milk quality genes. KEGG pathways analysis of potential cis and trans target genes of DE lncRNAs indicated that 27 and 48 pathways were significantly enriched in Kashmiri and Jersey respectively, including mTOR signaling, PI3K-Akt signaling and RAP1 signaling pathways. These pathways have been proven to play key roles in lactation biology and mammary gland development. Conclusions Our study mapped the expression profiles of lncRNAs across lactation stages and their relationships with candidate genes related to milk quality and yield traits in Jersey and Kashmiri cattle. These findings provide a valuable resource for the study of the regulatory mechanisms involved in the lactation process as well as facilitate understanding of the role of lncRNAs in bovine lactation biology.

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