scholarly journals Mammary Gland Development in Transforming Growth Factor Beta1 Null Mutant Mice: Systemic and Epithelial Effects1

2008 ◽  
Vol 79 (4) ◽  
pp. 711-717 ◽  
Author(s):  
Wendy V. Ingman ◽  
Sarah A. Robertson
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Mammary Gland Development ◽  
Transforming Growth Factor ◽  
Mutant Mice ◽  
Null Mutant ◽  
Transforming Growth Factor Beta1 ◽  
Null Mutant Mice ◽  
Gland Development

scholarly journals A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

2009 ◽  
Vol 29 (16) ◽  
pp. 4455-4466 ◽  
Author(s):  
Sarah M. Francis ◽  
Jacqueline Bergsied ◽  
Christian E. Isaac ◽  
Courtney H. Coschi ◽  
Alison L. Martens ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Growth Inhibition ◽  
Mammary Gland Development ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mammary Development ◽  
Functional Connection ◽  
Gland Development

ABSTRACT Transforming growth factor β (TGF-β) is a crucial mediator of breast development, and loss of TGF-β-induced growth arrest is a hallmark of breast cancer. TGF-β has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-β cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1 ΔL and Rb1NF ), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-β growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-β signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-β cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-β in growth control and mammary gland development.

The Liver in Transforming Growth Factor-Beta-1 (TGF-β1) Null Mutant Mice

1996 ◽  
Vol 20 (5) ◽  
pp. 477-490 ◽  
Author(s):  
A. Olufemi Williams ◽  
Alan D. Knapton ◽  
Andrew Geiser ◽  
John J. Letterio ◽  
Anita B. Roberts
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mutant Mice ◽  
Null Mutant ◽  
Growth Factor Beta ◽  
Null Mutant Mice ◽  
Tgf Β1

Exogenous transforming growth factor beta1 replacement and fertility in male Tgfb1 null mutant mice

2009 ◽  
Vol 21 (4) ◽  
pp. 561 ◽  
Author(s):  
Leanne J. McGrath ◽  
Wendy V. Ingman ◽  
Rebecca L. Robker ◽  
Sarah A. Robertson
Keyword(s):  
Growth Factor ◽  
Reproductive Tract ◽  
Transforming Growth Factor ◽  
Mating Behaviour ◽  
Bovine Milk ◽  
Reproductive Function ◽  
Serum Testosterone ◽  
Mutant Mice ◽  
Null Mutant ◽  
Null Mutant Mice

Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor β1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2; however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (~150 μg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum; however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.

301. Effect of exogenous transforming growth factor beta 1 on reproductive performance in male TGFβ1 null mice

2005 ◽  
Vol 17 (9) ◽  
pp. 128
Author(s):  
L. J. McGrath ◽  
R. Robker ◽  
S. A. Robertson
Keyword(s):  
Growth Factor ◽  
Reproductive Performance ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mating Behaviour ◽  
Mutant Mice ◽  
Null Mutant ◽  
Exogenous Cytokine ◽  
Growth Factor Beta ◽  
Null Mutant Mice

The transforming growth factor beta 1 (TGFβ1) family are potent cytokines that regulate tissue development, inflammation and immunity. Our studies in null mutant mice implicate a key role for TGFβ1 in male reproductive function. The TGFβ1 null mutation results in profound infertility due to inability to copulate successfully associated with reduced testosterone synthesis, although penile erection and sperm production do occur. To investigate whether fertility status can be improved in TGFβ1 null mutant mice by exogenous cytokine replacement, we used Alzet mini-pumps implanted subcutaneously to deliver a constant supply of recombinant latent TGFβ1 to TGFβ–/– mice (n = 7, 2.1µg/day over 2 weeks). Control TGFβ–/– mice (n = 6) and +/+ mice (n = 10) received pumps containing BSA carrier only. Circulating levels of TGFß1 were increased in TGFβ–/– mice and reached levels comparable to those seen in fertile heterozygote littermates. Increased circulating testosterone was evident in a proportion of TGFβ–/– mice after exogenous TGFβ replacement compared with untreated control mice. However, serum testosterone content was widely variable within all groups, so statistical significance was not achieved. Videotaping of nocturnal mating behaviour while caging treated males with normal receptive female mice showed that unlike TGFβ+/+ mice, which successfully mounted and intromitted, untreated TGFβ–/– mice failed to engage in normal mating behaviour. TGFβ–/– mice treated with exogenous cytokine were occasionally seen to intromit but less frequently than TGFβ+/+ controls. Ejaculation did not occur in any of the TGFβ–/– mice regardless of TGFβ replacement, compared with TGFβ+/+ mice where 8/10 mice ejaculated during the 2 h observation period. The trend towards improvement in both testosterone levels and copulation activity of the TGFβ1 null mice treated with exogenous cytokine suggests that systemic TGFβ1 availability may influence reproductive performance in male mice. However, since fertility was not restored by cytokine replacement, locally produced TGFβ in the reproductive tract and/or hypothalamic pituitary axis are also implicated in regulating fertility.

The Mechanistic Basis for Sexual Dysfunction in Male Transforming Growth Factor  1 Null Mutant Mice

2009 ◽  
Vol 31 (2) ◽  
pp. 95-107 ◽  
Author(s):  
W. V. Ingman ◽  
L. M. Mcgrath ◽  
W. G. Breed ◽  
I. F. Musgrave ◽  
R. L. Robker ◽  
...  
Keyword(s):  
Growth Factor ◽  
Sexual Dysfunction ◽  
Transforming Growth Factor ◽  
Mutant Mice ◽  
Null Mutant ◽  
Mechanistic Basis ◽  
Null Mutant Mice

scholarly journals Attenuated TGFB signalling in macrophages decreases susceptibility to DMBA-induced mammary cancer in mice

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Xuan Sun ◽  
Sarah M. Bernhardt ◽  
Danielle J. Glynn ◽  
Leigh J. Hodson ◽  
Lucy Woolford ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Cancer ◽  
Breast Tissue ◽  
Mammary Gland Development ◽  
Transforming Growth Factor ◽  
Cancer Susceptibility ◽  
Dominant Negative ◽  
Target Cells ◽  
Tumour Development ◽  
Gland Development

AbstractBackgroundTransforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. TGFB1 also plays roles in tumour development and progression, and its increased expression is associated with an increased breast cancer risk. Macrophages are key target cells for TGFB1 action, also playing crucial roles in tumourigenesis. However, the precise role of TGFB-regulated macrophages in the mammary gland is unclear. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice.MethodsA transgenic mouse model was generated, wherein a dominant negative TGFB receptor is activated in macrophages, in turn attenuating the TGFB signalling pathway specifically in the macrophage population. The mammary glands were assessed for morphological changes through wholemount and H&E analysis, and the abundance and phenotype of macrophages were analysed through immunohistochemistry. Another cohort of mice received carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), and tumour development was monitored weekly. Human non-neoplastic breast tissue was also immunohistochemically assessed for latent TGFB1 and macrophage marker CD68.ResultsAttenuation of TGFB signalling resulted in an increase in the percentage of alveolar epithelium in the mammary gland at dioestrus and an increase in macrophage abundance. The phenotype of macrophages was also altered, with inflammatory macrophage markers iNOS and CCR7 increased by 110% and 40%, respectively. A significant decrease in DMBA-induced mammary tumour incidence and prolonged tumour-free survival in mice with attenuated TGFB signalling were observed. In human non-neoplastic breast tissue, there was a significant inverse relationship between latent TGFB1 protein and CD68-positive macrophages.ConclusionsTGFB acts on macrophage populations in the mammary gland to reduce their abundance and dampen the inflammatory phenotype. TGFB signalling in macrophages increases mammary cancer susceptibility potentially through suppression of immune surveillance activities of macrophages.

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