HGF/SF: a potent cytokine for mammary growth, morphogenesis and development

Development ◽  
1995 ◽  
Vol 121 (9) ◽  
pp. 2897-2908 ◽  
Author(s):  
B. Niranjan ◽  
L. Buluwela ◽  
J. Yant ◽  
N. Perusinghe ◽  
A. Atherton ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Developmental Stages ◽  
Mammary Epithelial Cells ◽  
Myoepithelial Cells ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Cell Populations ◽  
Normal Mammary Gland ◽  
Luminal Cells ◽  
Human And Mouse

The mammary gland is a renewing tissue in which morphogenetic processes and differentiation occur cyclically during the menstrual cycle, pregnancy and lactation. These events have been shown to be dependent upon epithelial-mesenchymal interactions. Studies of the effects of individual factors, their cellular source and their target cell populations in the different developmental stages of the mammary gland are greatly facilitated by the accessibility of this organ and the application of new techniques that allow purification of the major epithelial and stromal components of this tissue. Here we demonstrate that HGF/SF and its cellular receptor, c-met, are expressed and regulated temporally during mouse mammary development and differentiation. We show that human and mouse mammary fibroblasts produce HGF/SF and that HGF/SF is not only mitogenic but morphogenic and motogenic for both human and mouse mammary epithelial cells. We have found that human luminal and myoepithelial cells express c-met differentially and that HGF/SF has different effects on these two mammary epithelial cell populations. HGF/SF is mitogenic for luminal cells but not myoepithelial cells, and morphogenic to myoepithelial cells but not luminal cells. This is discussed in the context of the proliferative compartments in the normal mammary gland and the potential role of the myoepithelial cells to act as the skeleton for ductal development.

scholarly journals MicroRNA in the ovine mammary gland during early pregnancy: spatial and temporal expression of miR-21, miR-205, and miR-200

2013 ◽  
Vol 45 (4) ◽  
pp. 151-161 ◽  
Author(s):  
Laurent Galio ◽  
Stéphanie Droineau ◽  
Patrick Yeboah ◽  
Hania Boudiaf ◽  
Stephan Bouet ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Early Pregnancy ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Normal Mammary Gland ◽  
Basal Cells ◽  
Pregnancy And Lactation ◽  
Luminal Cells

The mammary gland undergoes extensive remodeling between the beginning of pregnancy and lactation; this involves cellular processes including cell proliferation, differentiation, and apoptosis, all of which are under the control of numerous regulators. To unravel the role played by miRNA, we describe here 47 new ovine miRNA cloned from mammary gland in early pregnancy displaying strong similarities with those already identified in the cow, human, or mouse. A microarray study of miRNA variations in the adult ovine mammary gland during pregnancy and lactation showed that 100 miRNA are regulated according to three principal patterns of expression: a decrease in early pregnancy, a peak at midpregnancy, or an increase throughout late pregnancy and lactation. One miRNA displaying each pattern (miR-21, miR-205, and miR-200b) was analyzed by qRT-PCR. Variations in expression were confirmed for all three miRNA. Using in situ hybridization, we detected both miR-21 and miR-200 in luminal mammary epithelial cells when expressed, whereas miR-205 was expressed in basal cells during the first half of pregnancy and then in luminal cells during the second half. We therefore conclude that miR-21 is strongly expressed in the luminal cells of the normal mammary gland during early pregnancy when extensive cell proliferation occurs. In addition, we show that miR-205 and miR-200 are coexpressed in luminal cells, but only during the second half of pregnancy. These two miRNA may cooperate to maintain epithelial status by repressing an EMT-like program, to achieve and preserve the secretory phenotype of mammary epithelial cells.

scholarly journals Laminin alpha 5 regulates mammary gland remodeling through luminal cell differentiation and Wnt4-mediated epithelial crosstalk

Development ◽  
2021 ◽  
Vol 148 (12) ◽  
Author(s):  
Johanna I. Englund ◽  
Alexandra Ritchie ◽  
Leander Blaas ◽  
Hanne Cojoc ◽  
Nalle Pentinmikko ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Normal Mammary Gland ◽  
Reduced Frequency ◽  
Luminal Cells ◽  
Vitro Model

ABSTRACT Epithelial attachment to the basement membrane (BM) is essential for mammary gland development, yet the exact roles of specific BM components remain unclear. Here, we show that Laminin α5 (Lama5) expression specifically in the luminal epithelial cells is necessary for normal mammary gland growth during puberty, and for alveologenesis during pregnancy. Lama5 loss in the keratin 8-expressing cells results in reduced frequency and differentiation of hormone receptor expressing (HR+) luminal cells. Consequently, Wnt4-mediated crosstalk between HR+ luminal cells and basal epithelial cells is compromised during gland remodeling, and results in defective epithelial growth. The effects of Lama5 deletion on gland growth and branching can be rescued by Wnt4 supplementation in the in vitro model of branching morphogenesis. Our results reveal a surprising role for BM-protein expression in the luminal mammary epithelial cells, and highlight the function of Lama5 in mammary gland remodeling and luminal differentiation.

Developmental role of the SNF1-related kinase Hunk in pregnancy-induced changes in the mammary gland

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4493-4509
Author(s):  
H.P. Gardner ◽  
G.K. Belka ◽  
G.B. Wertheim ◽  
J.L. Hartman ◽  
S.I. Ha ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelium ◽  
Ovarian Hormones ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Serine Threonine Kinase ◽  
Proliferation And Differentiation ◽  
Induced Changes

The steroid hormones 17 beta-estradiol and progesterone play a central role in the pathogenesis of breast cancer and regulate key phases of mammary gland development. This suggests that developmental regulatory molecules whose activity is influenced by ovarian hormones may also contribute to mammary carcinogenesis. In a screen designed to identify protein kinases expressed in the mammary gland, we previously identified a novel SNF1-related serine/threonine kinase, Hunk (hormonally upregulated Neu-associated kinase). During postnatal mammary development, Hunk mRNA expression is restricted to a subset of mammary epithelial cells and is temporally regulated with highest levels of expression occurring during early pregnancy. In addition, treatment of mice with 17 beta-estradiol and progesterone results in the rapid and synergistic upregulation of Hunk expression in a subset of mammary epithelial cells, suggesting that the expression of this kinase may be regulated by ovarian hormones. Consistent with the tightly regulated pattern of Hunk expression during pregnancy, mammary glands from transgenic mice engineered to misexpress Hunk in the mammary epithelium manifest temporally distinct defects in epithelial proliferation and differentiation during pregnancy, and fail to undergo normal lobuloalveolar development. Together, these observations suggest that Hunk may contribute to changes in the mammary gland that occur during pregnancy in response to ovarian hormones.

scholarly journals The insulin receptor plays an important role in secretory differentiation in the mammary gland

2013 ◽  
Vol 305 (9) ◽  
pp. E1103-E1114 ◽  
Author(s):  
Margaret C. Neville ◽  
Patricia Webb ◽  
Palaniappan Ramanathan ◽  
Meridee P. Mannino ◽  
Chiara Pecorini ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Insulin Receptor ◽  
Lipid Droplets ◽  
Mammary Epithelial Cells ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Expression Of Genes ◽  
Lactating Mammary Gland ◽  
Development And Differentiation ◽  
Pregnant Mice

Insulin is known to be an important regulator of milk secretion in the lactating mammary gland. Here we examine the role of insulin signaling in mammary development in pregnancy using a mouse with a floxed insulin receptor (IR) crossed with a mouse expressing Cre specifically in the mammary gland. In the mammary glands of these IRfl/fl Cre+ mice, expression of IR is significantly diminished throughout development. Glands from these mice had 50% fewer alveoli at midpregnancy; casein and lipid droplets were diminished by 60 and 75%, respectively, indicating a role for IR both in alveolar development and differentiation. In an acinar preparation from mammary epithelial cells (MEC) isolated from pregnant mice, insulin stimulated lumen formation, mammary cell size, acinar size, acinar casein content, and the formation of lipid droplets with a Km of ∼1.7 nM. IGF-I and IGF-II had no effect at concentrations below 50 nM, and a function blocking antibody to the IGF type 1 receptor did not alter the response to insulin. We conclude that insulin interacting with IR is essential for mammary differentiation during murine pregnancy. Using array analysis, we then examined the expression of genes up- or downregulated >1.5-fold in the IRfl/fl Cre+ MECs, finding significant downregulation of differentiation specific genes and upregulation of cell cycle and extracellular matrix genes. We conclude that insulin fosters differentiation and may inhibit cell proliferation in the mammary gland of the midpregnant mouse.

scholarly journals NEW INSIGHTS OF MAMMARY GLAND DURING DIFFERENT STAGES OF DEVELOPMENT

2017 ◽  
Vol 10 (11) ◽  
pp. 35 ◽  
Author(s):  
Manoj Kumar Jena ◽  
Ashok Kumar Mohanty
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Developmental Stages ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Fine Tuning ◽  
Molecular Events ◽  
Mammary Gland Biology ◽  
Lactation Cycle ◽  
Gland Development

  Mammary gland is a unique organ with its function of milk synthesis, secretion, and involution to prepare the gland for subsequent lactation. The mammary epithelial cells proliferate, differentiate, undergo apoptosis, and tissue remodeling following a cyclic pathway in lactation – involution – lactation cycle, thus fine tuning the molecular events through hormones, and regulatory molecules. Several studies are performed on the mammary gland development, lactogenesis, and involution process in molecular details. The developmental stages of mammary gland are embryonic, pre-pubertal, pubertal, pregnancy, lactation, and involution. Major developmental processes occur after puberty with hormones and growth factors playing crucial role. The two major pathways such as Janus kinases-signal transducer and activator of transcription pathway and PI3K-Akt pathway play a major role in maintaining the lactation. The involution process is a well-orchestrated event involving several signaling molecules and making the gland ready for subsequent lactation. The review focuses on findings with molecular details of different stages of the mammary gland development and signaling pathways involved in lactation–involution cycle. Deep insight into the developmental stages of mammary gland will pave the way to understand mammary gland biology, apoptosis, oncogenesis, and it will help the researchers to use mammary gland as a model for research on various aspects.  

scholarly journals MicroRNAs in the development and neoplasia of the mammary gland

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1018
Author(s):  
Manoj Kumar Jena
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Mammary Gland ◽  
Cancer Progression ◽  
Developmental Stages ◽  
Mammary Epithelial Cells ◽  
Tumour Progression ◽  
Mammary Epithelial ◽  
Altered Expression

Study on the role of microRNAs (miRs) as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2) signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ERα, and ERα-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes. Oncogenic miRs like miR-21, miR-221, and miR-210 are overexpressed in triple negative breast cancer cases which can be diagnostic biomarker for this subtype of cancer.  This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages) and their involvement in breast cancer progression. Further studies in this area will help us to understand the molecular details of mammary gland biology, as well as miRs that could be therapeutic targets of breast cancer.

scholarly journals Photoperiod effects on milk production in goats: Are they mediated by the molecular clock in the mammary gland?

2014 ◽  
Author(s):  
Therese Casey ◽  
Sameer J. Mabjeesh ◽  
Avi Shamay ◽  
Karen Plaut
Keyword(s):  
Growth Rate ◽  
Mammary Gland ◽  
Epithelial Cell ◽  
Milk Production ◽  
Mammary Epithelial Cell ◽  
Mammary Epithelial Cells ◽  
Physiological State ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Protein Levels

US scientists, Dr. Theresa Casey and Dr. Karen Plaut, collaborated with Israeli scientists, Dr. SameerMabjeesh and Dr. AviShamay to conduct studies proposed in the BARD Project No. US-4715-14 Photoperiod effects on milk production in goats: Are they mediated by the molecular clock in the mammary gland over the last 3 years. CLOCK and BMAL1 are core components of the circadian clock and as heterodimers function as a transcription factor to drive circadian-rhythms of gene expression. Studies of CLOCK-mutant mice found impaired mammary development in late pregnancy was related to poor lactation performance post-partum. To gain a better understanding of role of clock in regulation of mammary development studies were conducted with the mammary epithelial cell line HC11. Decreasing CLOCK protein levels using shRNA resulted in increased mammary epithelial cell growth rate and impaired differentiation, with lower expression of differentiation markers including ad herens junction protein and fatty acid synthesis genes. When BMAL1 was knocked out using CRISPR-CAS mammary epithelial cells had greater growth rate, but reached stationary phase at a lower density, with FACS indicating cells were growing and dying at a faster rate. Beta-casein milk protein levels were significantly decreased in BMAL1 knockout cells. ChIP-seq analysis was conducted to identify BMAL1 target genes in mammary epithelial cells. Studies conducted in goats found that photoperiod duration and physiological state affected the dynamics of the mammary clock. Effects were likely independent of the photoperiod effects on prolactin levels. Interestingly, circadian rhythms of core body temperature, which functions as a key synchronizing cue sent out by the central clock in the hypothalamus, were profoundly affected by photoperiod and physiological state. Data support that the clock in the mammary gland regulates genes important to development of the gland and milk synthesis. We also found the clock in the mammary is responsive to changes in physiological state and photoperiod, and thus may serve as a mechanism to establish milk production levels in response to environmental cues. 

Differential regulation of GLUT1 and GLUT8 expression by hypoxia in mammary epithelial cells

2014 ◽  
Vol 307 (3) ◽  
pp. R237-R247 ◽  
Author(s):  
Yong Shao ◽  
Theresa L. Wellman ◽  
Karen M. Lounsbury ◽  
Feng-Qi Zhao
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Glucose Uptake ◽  
Mammary Epithelial Cells ◽  
Physiological Mechanism ◽  
Glucose Transporters ◽  
Mammary Glands ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Early Lactation

Glucose is a major substrate for milk synthesis and is taken up from the blood by mammary epithelial cells (MECs) through facilitative glucose transporters (GLUTs). The expression levels of GLUT1 and GLUT8 are upregulated dramatically in the mammary gland from late pregnancy through early lactation stages. This study aimed to test the hypothesis that this increase in GLUT1 and GLUT8 expression involves hypoxia signaling through hypoxia inducible factor-1α (HIF-1α) in MECs. Mouse mammary glands showed significantly more hypoxia in midpregnancy through early lactation stages compared with in the virgin stage, as stained by the hypoxia marker pimonidazole HCl. Treatment with hypoxia (2% O2) significantly stimulated glucose uptake and GLUT1 mRNA and protein expression, but decreased GLUT8 mRNA expression in bovine MECs. In MECs, hypoxia also increased the levels of HIF-1α protein in the nuclei, and siRNA against HIF-1α completely abolished the hypoxia-induced upregulation of GLUT1, while having no effect on GLUT8 expression. A 5′-RCGTG-3′ core HIF-1α binding sequence was identified 3.7 kb upstream of the bovine GLUT1 gene, and HIF-1α binding to this site was increased during hypoxia. In conclusion, the mammary glands in pregnant and lactating animals are hypoxic, and MECs respond to this hypoxia by increasing GLUT1 expression and glucose uptake through a HIF-1α-dependent mechanism. GLUT8 expression, however, is negatively regulated by hypoxia through a HIF-1α-independent pathway. The regulation of glucose transporters through hypoxia-mediated gene transcription in the mammary gland may provide an important physiological mechanism for MECs to meet the metabolic demands of mammary development and lactation.

scholarly journals Elevated Circulating IGF-I Promotes Mammary Gland Development and Proliferation

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5751-5761 ◽  
Author(s):  
Dara Cannata ◽  
Danielle Lann ◽  
Yingjie Wu ◽  
Sebastien Elis ◽  
Hui Sun ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Animal Studies ◽  
Mammary Gland Development ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Epithelial Development ◽  
Igf I ◽  
Luminal Cells ◽  
Gland Development ◽  
Major Mediator

Animal studies have shown that IGF-I is essential for mammary gland development. Previous studies have suggested that local IGF-I rather than circulating IGF-I is the major mediator of mammary gland development. In the present study we used the hepatic IGF-I transgenic (HIT) and IGF-I knockout/HIT (KO-HIT) mouse models to examine the effects of enhanced circulating IGF-I on mammary development in the presence and absence of local IGF-I. HIT mice express the rat IGF-I transgene under the transthyretin promoter in the liver and have elevated circulating IGF-I and normal tissue IGF-I levels. The KO-HIT mice have no tissue IGF-I and increased circulating IGF-I. Analysis of mammary gland development reveals a greater degree of complexity in HIT mice as compared to control and KO-HIT mice, which demonstrate similar degrees of mammary gland complexity. Immunohistochemical evaluation of glands of HIT mice also suggests an enhanced degree of proliferation of the mammary gland, whereas KO-HIT mice exhibit mammary gland proliferation similar to control mice. In addition, HIT mice have a higher percentage of proliferating myoepithelial and luminal cells than control mice, whereas KO-HIT mice have an equivalent percentage of proliferating myoepithelial and luminal cells as control mice. Thus, our findings show that elevated circulating IGF-I levels are sufficient to promote normal pubertal mammary epithelial development. However, HIT mice demonstrate more pronounced mammary gland development when compared to control and KO-HIT mice. This suggests that both local and endocrine IGF-I play roles in mammary gland development and that elevated circulating IGF-I accelerates mammary epithelial proliferation.

scholarly journals Differential transformation of mammary epithelial cells by Wnt genes.

1994 ◽  
Vol 14 (9) ◽  
pp. 6278-6286 ◽  
Author(s):  
G T Wong ◽  
B J Gavin ◽  
A P McMahon
Keyword(s):  
Mammary Gland ◽  
Mammary Epithelial Cells ◽  
Family Members ◽  
Mammary Epithelial ◽  
Mammary Tissue ◽  
Epithelial Cell Line ◽  
Normal Mammary Gland ◽  
Morphological Transformation ◽  
Apparent Decrease ◽  
Tumor Virus

The mouse Wnt family includes at least 10 genes that encode structurally related secreted glycoproteins. Wnt-1 and Wnt-3 were originally identified as oncogenes activated by the insertion of mouse mammary tumor virus in virus-induced mammary adenocarcinomas, although they are not expressed in the normal mammary gland. However, five other Wnt genes are differentially expressed during development of adult mammary tissue, suggesting that they may play distinct roles in various phases of mammary gland growth and development. Induction of transformation by Wnt-1 and Wnt-3 may be due to interference with these normal regulatory events; however, there is no direct evidence for this hypothesis. We have tested Wnt family members for the ability to induce transformation of cultured mammary cells. The results demonstrate that the Wnt gene family can be divided into three groups depending on their ability to induce morphological transformation and altered growth characteristics of the C57MG mammary epithelial cell line. Wnt-1, Wnt-3A, and Wnt-7A were highly transforming and induced colonies which formed and shed balls of cells. Wnt-2, Wnt-5B, and Wnt-7B also induced transformation but with a lower frequency and an apparent decrease in saturation density. In contrast, Wnt-6 and two other family members which are normally expressed in C57MG cells, Wnt-4 and Wnt-5A, failed to induce transformation. These data demonstrate that the Wnt genes have distinct effects on cell growth and should not be regarded as functionally equivalent.

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