scholarly journals Epithelial-Specific and Stage-Specific Functions of Insulin-Like Growth Factor-I during Postnatal Mammary Development

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5412-5423 ◽  
Author(s):  
Aimee V. Loladze ◽  
Malinda A. Stull ◽  
Anne M. Rowzee ◽  
Jean DeMarco ◽  
James H. Lantry ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Postnatal Development ◽  
Alveolar Epithelium ◽  
Mammary Epithelium ◽  
Gene Promoter ◽  
Mammary Development ◽  
Protein Levels ◽  
Pubertal Growth ◽  
Igf I ◽  
Mouse Lines

Postnatal development of the mammary gland requires interactions between the epithelial and stromal compartments, which regulate actions of hormones and growth factors. IGF-I is expressed in both epithelial and stromal compartments during postnatal development of the mammary gland. However, little is known about how local expression of IGF-I in epithelium or stroma regulates mammary growth and differentiation during puberty and pregnancy-induced alveolar development. The goal of this study was to investigate the mechanisms of IGF-I actions in the postnatal mammary gland and test the hypothesis that IGF-I expressed in stromal and epithelial compartments has distinct functions. We established mouse lines with inactivation of the igf1 gene in mammary epithelium by crossing igf1/loxP mice with mouse lines expressing Cre recombinase under the control of either the mouse mammary tumor virus long-terminal repeat or the whey acidic protein gene promoter. Epithelial-specific loss of IGF-I during pubertal growth resulted in deficits in ductal branching. In contrast, heterozygous reduction of IGF-I throughout the gland decreased expression of cyclins A2 and B1 during pubertal growth and resulted in alterations in proliferation of the alveolar epithelium and milk protein levels during pregnancy-induced differentiation. Reduction in epithelial IGF-I at either of these stages had no effect on these indices. Taken together, our results support distinct roles for IGF-I expressed in epithelial and stromal compartments in mediating growth of the postnatal mammary gland.

scholarly journals Loss of vitamin D receptor signaling from the mammary epithelium or adipose tissue alters pubertal glandular development

2014 ◽  
Vol 307 (8) ◽  
pp. E674-E685 ◽  
Author(s):  
Abby L. Johnson ◽  
Glendon M. Zinser ◽  
Susan E. Waltz
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Mammary Gland ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Mammary Epithelium ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Cell Type ◽  
Pubertal Mammary Development

Vitamin D3 receptor (VDR) signaling within the mammary gland regulates various postnatal stages of glandular development, including puberty, pregnancy, involution, and tumorigenesis. Previous studies have shown that vitamin D3 treatment induces cell-autonomous growth inhibition and differentiation of mammary epithelial cells in culture. Furthermore, mammary adipose tissue serves as a depot for vitamin D3 storage, and both epithelial cells and adipocytes are capable of bioactivating vitamin D3. Despite the pervasiveness of VDR in mammary tissue, individual contributions of epithelial cells and adipocytes, as well as the VDR-regulated cross-talk between these two cell types during pubertal mammary development, have yet to be investigated. To assess the cell-type specific effect of VDR signaling during pubertal mammary development, novel mouse models with mammary epithelial- or adipocyte-specific loss of VDR were generated. Interestingly, loss of VDR in either cellular compartment accelerated ductal morphogenesis with increased epithelial cell proliferation and decreased apoptosis within terminal end buds. Conversely, VDR signaling specifically in the mammary epithelium modulated hormone-induced alveolar growth, as ablation of VDR in this cell type resulted in precocious alveolar development. In examining cellular cross-talk ex vivo, we show that ligand-dependent VDR signaling in adipocytes significantly inhibits mammary epithelial cell growth in part through the vitamin D3-dependent production of the cytokine IL-6. Collectively, these studies delineate independent roles for vitamin D3-dependent VDR signaling in mammary adipocytes and epithelial cells in controlling pubertal mammary gland development.

Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution

Development ◽  
2000 ◽  
Vol 127 (14) ◽  
pp. 3107-3118 ◽  
Author(s):  
A.V. Nguyen ◽  
J.W. Pollard
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Transforming Growth Factor ◽  
Alveolar Epithelium ◽  
Mammary Epithelium ◽  
Significant Inhibition ◽  
Mammary Tissue ◽  
Lactogenic Hormone ◽  
Null Mutant Mice ◽  
Transforming Growth Factor Beta3

Involution of the mammary gland following weaning is divided into two distinct phases. Initially, milk stasis results in the induction of local factors that cause apoptosis in the alveolar epithelium. Secondly after a prolonged absence of suckling, the consequent decline in circulating lactogenic hormone concentrations initiates remodeling of the mammary gland to the virgin-like state. We have shown that immediately following weaning TGFbeta3 mRNA and protein is rapidly induced in the mammary epithelium and that this precedes the onset of apoptosis. Unilateral inhibition of suckling and hormonal reconstitution experiments showed that TGFbeta3 induction is regulated by milk stasis and not by the circulating hormonal concentration. Directed expression of TGFbeta3 in the alveolar epithelium of lactating mice using a beta-lactoglobulin promoter mobilized SMAD4 translocation to the nucleus and caused apoptosis of these cells, but not tissue remodeling. Transplantation of neonatal mammary tissue derived from TGFbeta3 null mutant mice into syngenic hosts resulted in a significant inhibition of cell death compared to wild-type mice upon milk stasis. These results provide direct evidence that TGFbeta3 is a local mammary factor induced by milk stasis that causes apoptosis in the mammary gland epithelium during involution.

scholarly journals The expression of the IGF family and GH receptor in the bovine mammary gland

2001 ◽  
Vol 168 (1) ◽  
pp. 39-48 ◽  
Author(s):  
A Plath-Gabler ◽  
C Gabler ◽  
F Sinowatz ◽  
B Berisha ◽  
D Schams
Keyword(s):  
Mammary Gland ◽  
Binding Proteins ◽  
Mammary Development ◽  
Mammary Tissue ◽  
Bovine Mammary Gland ◽  
Igf Binding Proteins ◽  
Gh Receptor ◽  
Igf I ◽  
Temporal Expressions ◽  
Igfbp 3

To study the involvement of the IGFs in mammary development and lactation of the cow, the temporal expressions of IGF-I and -II, its receptor type 1 (IGFR-1), IGF-binding proteins (IGFBPs)-1 to -6 and GH receptor (GHR) mRNA were examined. This was carried out for different stages of mammogenesis, lactogenesis, galactopoiesis and involution in the bovine mammary gland of 26 animals. Furthermore, IGF-I was localised by immunohistochemistry. The highest mRNA concentrations for IGF-I were detected in the mammary tissue of late pregnant heifers (days 255-272) and significantly lower expression was detected during lactogenesis and galactopoiesis. Immunohistochemistry of IGF-I revealed only a weak staining in the epithelium of the ducts during mammogenesis. The epithelium of the alveoli were negative during mammogenesis, lactogenesis and galactopoiesis but displayed distinct IGF-I activity during involution. In the stroma a distinct staining of the cytoplasm of adipocytes and of vascular smooth muscle cells was observed. A certain percentage of fibroblasts (usually 20-30%) were also immunopositive. In contrast, highest expression for IGFR-1 was detected during galactopoiesis and involution. The lowest mRNA concentration for IGFR-1 was found during pregnancy (days 194-213). In general, the expression of IGF-II was not regulated during mammogenesis and lactation, but decreased during involution. The mRNA for the six binding proteins was detected in the bovine mammary gland. The dominant binding proteins were IGFBP-3 and -5. The highest expression of IGFBP-3 was observed during mid-pregnancy and the lowest during late lactation, involution and in non-pregnant heifers. The mRNA for IGFBP-5 increased during late mammogenesis and lactogenesis followed by a decrease thereafter. In general, the mRNA concentrations for IGFBP-2, -4 and -6 were barely detectable during all stages. In contrast, the expression for IGFBP-1 was upregulated in the mammary gland of virgin heifers and increased around the onset of lactation. mRNA for GHR was found during all stages examined without outstanding fluctuations. In conclusion, locally produced IGF-I and -II may mediate mammogenesis. The high mammary IGFR-1 mRNA during lactation suggests a role for peripheral IGF-I in maintenance of lactation. The role of IGFBPs in the mammary gland needs further evaluation.

scholarly journals Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions

2008 ◽  
Vol 30 (1) ◽  
pp. 51-74 ◽  
Author(s):  
David L. Kleinberg ◽  
Teresa L. Wood ◽  
Priscilla A. Furth ◽  
Adrian V. Lee
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Growth Factors ◽  
Mammary Development ◽  
Main Role ◽  
Precursor Lesions ◽  
Igf Binding Proteins ◽  
Genetic Imprinting ◽  
Igf I

Abstract Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations.

scholarly journals Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice

Development ◽  
2002 ◽  
Vol 129 (19) ◽  
pp. 4547-4557 ◽  
Author(s):  
Elizabeth Tonner ◽  
Michael C. Barber ◽  
Gordon J. Allan ◽  
James Beattie ◽  
John Webster ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Death ◽  
Mammary Gland ◽  
Transgenic Mice ◽  
Dna Content ◽  
Caspase 3 ◽  
Transgenic Animals ◽  
Mammary Glands ◽  
Mammary Development ◽  
Igf I

We have previously demonstrated that IGFBP-5 production by mammary epithelial cells increases dramatically during involution of the mammary gland. To demonstrate a causal relationship between IGFBP-5 and cell death we created transgenic mice expressing IGFBP-5 in the mammary gland using a mammary-specific promoter, β-lactoglobulin. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy. Histological analysis indicated reduced numbers of alveolar end buds, with decreased ductal branching. Transgenic dams produced IGFBP-5 in their milk at concentrations similar to those achieved at the end of normal lactation. Mammary cell number and milk synthesis were both decreased by approximately 50% during the first 10 days of lactation. BrdU labelling was decreased, whereas DNA ladders were increased in transgenic animals on day 1 of lactation. On day 2 postpartum, the epithelial invasion of the mammary fat pad was clearly impaired in transgenic animals. The concentrations of the pro-apoptotic molecule caspase-3 and of plasmin were both increased in transgenic animals whilst the concentrations of 2 prosurvival molecules Bcl-2 and Bcl-xLwere both decreased. In order to examine whether IGFBP-5 acts by inhibiting the survival effect of IGF-I we examined IGF receptor phosphorylation and Akt phosphorylation and showed that both were inhibited. We attempted to “rescue” the transgenic phenotype by using growth hormone to increase endogenous IGF-I concentrations or by implanting minipumps delivering an IGF-1 analogue, R3-IGF-1, which binds weakly to IGFBP-5. Growth hormone treatment failed to affect mammary development suggesting that increased concentrations of endogenous IGF-1 are insufficient to overcome the high concentrations of IGFBP-5 produced by these transgenic animals. In contrast mammary development (gland weight and DNA content) was normalised by R3-IGF-I although milk production was only partially restored. This is the first demonstration that over-expression of IGFBP-5 can lead to; impaired mammary development, increased expression of the pro-apoptotic molecule caspase-3, increased plasmin generation and decreased expression of pro-survival molecules of the Bcl-2 family. It clearly demonstrates that IGF-I is an important developmental/survival factor for the mammary gland and, furthermore, this cell death programme may be utilised in a wide variety of tissues.

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 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. 

Effect of feeding level during the prepubertal phase on mammary gland development in female goat kids

2019 ◽  
Vol 86 (3) ◽  
pp. 267-271
Author(s):  
Clemence Panzuti ◽  
Christine Duvaux-Ponter ◽  
Rupert M. Bruckmaier ◽  
Frederic Dessauge
Keyword(s):  
Mammary Gland ◽  
Positive Impact ◽  
Mammary Development ◽  
The Body ◽  
Early Weaning ◽  
Feeding Level ◽  
Body Development ◽  
Igf I ◽  
Gland Development ◽  
Concentrate Level

AbstractThe experiment reported in this research communication aimed to determine the effects of post-weaning feeding level after early weaning on mammary parenchyma development in Alpine goats. Thirty Alpine female goat kids were weaned early (at around 9.8 kg and 32 d of age) and fed different levels of concentrate: Control (C, 730 g DM/d, n = 10), Low (L, 365 g DM/d, n = 10) or High (H, 1090 g DM/d, n = 10) until 235 d of age with ad libitum hay and water. Half of the goat kids were slaughtered before puberty (at around 208 d of age) and half at midgestation (at around 308 d of age and 70 d of gestation) for mammary parenchyma sampling. A histological analysis, Western blot and DNA quantification were performed. Blood samples were taken before puberty and at midgestation to determine plasma levels of IGF-I and prolactin. The mammary gland weights before puberty and at midgestation were positively and significantly associated with concentrate level. However, the organization of the mammary parenchyma and protein expression and quantity of DNA in the parenchyma were similar among the three groups. Before puberty, prolactin and IGF-I concentrations were significantly increased by the feeding level. In conclusion, feeding level after early weaning did not impact mammary parenchyma structure although it modified the weight of the mammary gland. The establishment of the mammary gland was not impacted by rearing management before puberty. Hence, increasing the feeding level during the rearing period could be an interesting way to increase the body development of goats without impairing mammary development whilst having a positive impact on reproductive parameters such as litter weight.

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.

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