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 Developmental regulation of Bcl-2 family protein expression in the involuting mammary gland

1999 ◽  
Vol 112 (11) ◽  
pp. 1771-1783 ◽  
Author(s):  
A.D. Metcalfe ◽  
A. Gilmore ◽  
T. Klinowska ◽  
J. Oliver ◽  
A.J. Valentijn ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
De Novo ◽  
Mammary Epithelial Cells ◽  
Expression Profiles ◽  
Mammary Epithelial ◽  
Mammary Tissue ◽  
Pregnancy And Lactation

Epithelial cells within the mammary gland undergo developmental programmes of proliferation and apoptosis during the pregnancy cycle. After weaning, secretory epithelial cells are removed by apoptosis. To determine whether members of the Bcl-2 gene family could be involved in regulating this process, we have examined whether changes in their expression occur during this developmental apoptotic program in vivo. Bax and Bcl-x were evenly expressed throughout development. However, expression of Bak and Bad was increased during late pregnancy and lactation, and the proteins were present during the time of maximal apoptotic involution. Thereafter, their levels declined. In contrast, Bcl-w was expressed in pregnancy and lactation but was downregulated at the onset of apoptosis. Bcl-2 was not detected in lactating or early involuting mammary gland. Thus, the pro-apoptotic proteins Bax, Bak and Bad, as well as the death-suppressors Bcl-x, Bcl-2 and Bcl-w, are synthesised in mouse mammary gland, and dynamic changes in the expression profiles of these proteins occurs during development. To determine if changes in Bak and Bcl-w expression could regulate mammary apoptosis, their effect on cultured mouse mammary epithelial cells was examined in transient transfection assays. Enforced expression of Bak induced rapid mammary apoptosis, which could be suppressed by coexpression of Bcl-w. In extracts of mammary tissue in vivo, Bak heterodimerized with Bcl-x whereas Bax associated with Bcl-w, but Bak/Bcl-w heterodimers were not detected. Thus, Bak and Bcl-w may regulate cell death through independent pathways. These results support a model in which mammary epithelial cells are primed for apoptosis during the transition from pregnancy to lactation by de novo expression of the death effectors Bak and Bad. It is suggested that these proteins are prevented from triggering apoptosis by anti-apoptotic Bcl-2 family proteins until involution, when the levels of Bcl-w decline. Our study provides evidence that regulated changes in the expression of cell death genes may contribute to the developmental control of mammary apoptosis.

scholarly journals Cellular localisation of GH receptor in the bovine mammary gland during mammogenesis, lactation and involution

2000 ◽  
Vol 166 (3) ◽  
pp. 503-510 ◽  
Author(s):  
F Sinowatz ◽  
D Schams ◽  
S Kolle ◽  
A Plath ◽  
D Lincoln ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Post Partum ◽  
In Situ Hybridisation ◽  
Alveolar Epithelium ◽  
Mammary Tissue ◽  
Bovine Mammary Gland ◽  
Direct Role ◽  
Gh Receptor ◽  
Gh Receptors

We have used immunohistochemistry and non-radioactive in situ hybridisation to localise the GH receptor and its transcript in the bovine mammary gland during mammogenesis, lactation and involution. We found a characteristic pattern of immunoreactive GH (irGH) receptor distribution in the epithelial and stromal compartments during the different stages of mammary gland development: The ductular epithelium showed a distinct staining for irGH receptor during most stages, whereas the alveolar epithelium contained a modest amount of GH receptor during pregnancy which increased during lactation and galactopoiesis. In dry cows, the immunostaining for GH receptors in the alveolar epithelium was very weak or negative. Curiously, the amount of GH receptor mRNA appeared relatively constant during mammogenesis and lactation. The epithelial cells of the alveoli and ducts as well as the endothelial cells showed a distinct signal in our in situ hy! bridisation studies. The predominant localisation of GH receptors in the epithelium of ducts and alveoli is supportive of a role for GH in epithelial differentiation and maintenance. Furthermore, the increased intensity of immunostaining in bovine mammary tissue post partum suggests a direct role for GH receptor in mediating the effect of GH in milk production and secretion.

scholarly journals Study of the action of tamoxifen on the mammary gland epithelium of premenopausal patients by lysosome quantification

1997 ◽  
Vol 115 (2) ◽  
pp. 1390-1394
Author(s):  
Carlos ltio Tanaka ◽  
Luiz Henrique Gebrim ◽  
Geraldo Rodrigues de Lima ◽  
Manuel de Jesus Simões
Keyword(s):  
Mammary Gland ◽  
Randomized Study ◽  
Mammary Epithelium ◽  
Hormonal Treatment ◽  
Primary Prophylaxis ◽  
Mammary Tissue ◽  
Early Effect ◽  
Adjuvant Hormonal Treatment ◽  
Premenopausal Patients ◽  
Cytochemical Technique

Tamoxifen is an antiestrogen drug widely utilized for the adjuvant hormonal treatment of breast carcinoma. Its use in the primary prophylaxis of this disease is currently being proposed. Although the drug has few side effects, its precise action on breast tissue that has not undergone neoplastic transformation has not been fully elucidated. This prospective, randomized study assessed the estrogen activity of tamoxifen on the mammary gland epithelium of premenopausal patients using a quantitative analysis of mammary epithelium lysosomes identified by the cytochemical technique of GOMORI for acid phosphatase and by light microscopy. Tamoxifen significantly increased the number of lysosomes only during the secretory phase of the menstrual cycle. We concluded that the early effect of the drug on normal mammary tissue is synergistic with the effect of estrogen during the premenopausal period.

scholarly journals Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

2016 ◽  
Vol 36 (11) ◽  
pp. 1673-1690 ◽  
Author(s):  
Kazuhito Sakamoto ◽  
Barbara L. Wehde ◽  
Kyung Hyun Yoo ◽  
Taemook Kim ◽  
Nirakar Rajbhandari ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Tyrosine Kinase ◽  
Inflammatory Cytokine ◽  
Target Genes ◽  
Mammary Epithelium ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Double Knockout ◽  
Downstream Effector

Despite a wealth of knowledge about the significance of individual signal transducers and activators of transcription (STATs), essential functions of their upstream Janus kinases (JAKs) during postnatal development are less well defined. Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyrosine kinase is essential for the activation of STAT1, STAT3, and STAT6 in the mammary epithelium. The loss of JAK1 uncouples interleukin-6-class ligands from their downstream effector, STAT3, which leads to the decreased expression of STAT3 target genes that are associated with the acute-phase response, inflammation, and wound healing. Consequently, JAK1-deficient mice exhibit impaired apoptosis and a significant delay in mammary gland remodeling. Using RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution. These includeBmfandBim, which are known regulators of programmed cell death. Using a BMF/BIM-double-knockout epithelial transplant model, we further validated that the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mammary epithelium. The collective results of this study suggest that JAK1 has nonredundant roles in the activation of particular STAT proteins and this tyrosine kinase is essential for coupling inflammatory cytokine signals to the cell death machinery in the differentiated mammary epithelium.

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 Inactivation of Stat5 in Mouse Mammary Epithelium during Pregnancy Reveals Distinct Functions in Cell Proliferation, Survival, and Differentiation

2004 ◽  
Vol 24 (18) ◽  
pp. 8037-8047 ◽  
Author(s):  
Yongzhi Cui ◽  
Greg Riedlinger ◽  
Keiko Miyoshi ◽  
Wei Tang ◽  
Cuiling Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Mammary Gland ◽  
Mammary Epithelium ◽  
Mouse Mammary Gland ◽  
Signal Transducers ◽  
Proliferation And Differentiation ◽  
Transgenic Lines ◽  
Mammary Gland Morphogenesis ◽  
Gland Morphogenesis

ABSTRACT This study explored the functions of the signal transducers and activators of transcription 5a and 5b (referred to as Stat5 here) during different stages of mouse mammary gland development by using conditional gene inactivation. Mammary gland morphogenesis includes cell specification, proliferation and differentiation during pregnancy, cell survival and maintenance of differentiation throughout lactation, and cell death during involution. Stat5 is activated by prolactin, and its presence is mandatory for the proliferation and differentiation of mammary epithelium during pregnancy. To address the question of whether Stat5 is also necessary for the maintenance and survival of the differentiated epithelium, the two genes were deleted at different time points. The 110-kb Stat5 locus in the mouse was bracketed with loxP sites, and its deletion was accomplished by using two Cre-expressing transgenic lines. Loss of Stat5 prior to pregnancy prevented epithelial proliferation and differentiation. Deletion of Stat5 during pregnancy, after mammary epithelium had entered Stat5-mediated differentiation, resulted in premature cell death, indicating that at this stage epithelial cell proliferation, differentiation, and survival require Stat5.

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.

Immunolocalization and Correlation Frequencies of Lingual Antimicrobial Peptide and Lactoferrin in Bovine Alveolar Epithelium and Bovine Mammary Gland

2013 ◽  
Vol 781-784 ◽  
pp. 699-708
Author(s):  
Ya Qiong Huang ◽  
Naoki Isobe ◽  
Yukinori Yoshimura ◽  
Kenji Hosoda
Keyword(s):  
Innate Immunity ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Antimicrobial Peptide ◽  
Immune Function ◽  
Time Course ◽  
Mammary Epithelial Cells ◽  
Alveolar Epithelium ◽  
Antigen Retrieval ◽  
Mammary Tissue

Mastitis is most critical disease in dairy cows and causes huge cost in the dairy industry. To prevent and treat it, it is important to understand the mechanisms of immune function in the mammary gland. Innate immunity is non-specific acute-response immune function. Some components of innate immunity in the mammary gland are found, e.g. Lingual Antimicrobial Peptide (LAP), Lactoferrin (LF). These components are found to be localized in the alveolar epithelium of mammary gland. LAP belongs to the β-defensin family, and plays a crucial role in killing a large variety of microorganisms. LF belongs to an iron-binding glycoprotein and has antibacterial activity. It is reported that LF has been localized immunohistochemically in mammary epithelial cells of lactating cows. Our previous study revealed that secretion of LAP into milk proceeded to that of LF after lipopolysaccharide (LPS) injection into the mammary gland. From this result, it is hypothesized that immunohistochemistry probably shows positive to either LF or LAP but not both in the alveolus vs epithelium in the mammary gland. Therefore, the aim of the present study is to investigate the immunolocalization of LAP and LF in the same bovine mammary tissue. Bovine mammary tissues were collected in the slaughterhouse and were fixed with neutralized formalin immediately. Paraffin sections (2-um thickness) were processed with antigen retrieval treatment followed by blocking with casein milk. Sections were cultured with LF antibody or LAP antibody. Immunoreaction products were visualized by incubation with a DAB. LAP and LF were localized in the cytoplasm of epithelial cell of alveolus. In some cases, LAP and LF were seen clearly in the same alveoli of section. In other cases, some epithelial cells were stained only LAP, but not LF, and other epithelial cells of alveolus were stained only LF, but not LAP. These results suggest the possibility that LAP and LF are differentially synthesized in the alveolar epithelium and may support our previous findings that their secretion occurs at the different time course.

The central nervous system, neurohypophysis and milk ejection

1958 ◽  
Vol 149 (936) ◽  
pp. 336-353 ◽  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mammary Gland ◽  
Alveolar Epithelium ◽  
Mammary Tissue ◽  
Milk Secretion ◽  
Active Process ◽  
Milk Ejection ◽  
The Central Nervous System ◽  
Passive Withdrawal

Lactation may be divided into two main phases. First, milk secretion which consists of the synthesis of milk by the cells of the alveolar epithelium and the passage of the milk from the cytoplasm of these cells into the alveolar lumen. And secondly, milk removal from the mammary gland. A small part of the milk may be withdrawn from the mammary gland by suckling young in the absence of any active process on the part of the maternal animal, passive withdrawal ; but the greater part of the contained milk requires for its removal the participation of a neurohumoral reflex resulting in contraction of mammary tissue and thereby expulsion of contained milk. This active process is called milk ejection .

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