scholarly journals ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5588
Author(s):  
Cristian Suarez-Cabrera ◽  
Isabel Ojeda-Perez ◽  
Raquel Sanchez-Baltasar ◽  
Angustias Page ◽  
Ana Bravo ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Transgenic Mice ◽  
Es Cells ◽  
Tumor Development ◽  
Human Tumor ◽  
Mammary Glands ◽  
Basal Cells ◽  
Differentiation Markers ◽  
Biochemical Alterations ◽  
Ras Superfamily

ERAS is a relatively uncharacterized gene of the Ras superfamily. It is expressed in ES cells and in the first stages of embryonic development; later on, it is silenced in the majority of cell types and tissues. Although there are several reports showing ERAS expression in tumoral cell lines and human tumor samples, it is unknown if ERAS deregulated expression is enough to drive tumor development. In this report, we have generated transgenic mice expressing ERAS in myoepithelial basal cells of the mammary gland and in basal cells of stratified epithelia. In spite of the low level of ERAS expression, these transgenic mice showed phenotypic alterations resembling overgrowth syndromes caused by the activation of the AKT-PI3K pathway. In addition, their mammary glands present developmental and functional disabilities accompanied by morphological and biochemical alterations in the myoepithelial cells. These mice suffer from tumoral transformation in the mammary glands with high incidence. These mammary tumors resemble, both histologically and by the expression of differentiation markers, malignant adenomyoepitheliomas. In sum, our results highlight the importance of ERAS silencing in adult tissues and define a truly oncogenic role for ERAS in mammary gland cells when inappropriately expressed.

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.

scholarly journals Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase

2002 ◽  
Vol 115 (1) ◽  
pp. 25-37
Author(s):  
Nadia Munarini ◽  
Richard Jäger ◽  
Susanne Abderhalden ◽  
Gisela Zuercher ◽  
Valeria Rohrbach ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Transgenic Mice ◽  
Apoptotic Cell ◽  
Mammary Epithelium ◽  
Transgenic Animals ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Mammary Epithelial ◽  
Cellular Growth ◽  
Mmtv Ltr

We have previously documented the cell-type-specific and hormone-dependent expression of the EphB4 receptor in the mouse mammary gland. To investigate its role in the biology of the mammary gland, we have established transgenic mice bearing the EphB4 receptor under the control of the MMTV-LTR promoter, which represents the first transgenic mouse model to investigate the effect(s) of unscheduled expression of EphB4 in adult organisms. Transgene expression in the mammary epithelium was induced at puberty, increased during pregnancy, culminated at early lactation and persisted until day three of post-lactational involution. In contrast, expression of the endogenous EphB4 gene is downregulated during pregnancy, is essentially absent during lactation and is re-induced after day three of post-lactational involution. The unscheduled expression of EphB4 led to a delayed development of the mammary epithelium at puberty and during pregnancy. During pregnancy, less lobules were formed, these however exhibited more numerous but smaller alveolar units. Transgenic mammary glands were characterized by a fragile, irregular morphology at lactation; however, sufficient functionality was maintained to nourish the young. Transgenic mammary glands exhibited untimely epithelial apoptotic cell death during pregnancy and abnormal epithelial DNA synthesis at early post-lactational involution, indicating a disturbed response to proliferative/apoptotic signals. Mammary tumours were not observed in the EphB4 transgenic animals; however, in double transgenic animals expressing both EphB4 and the neuT genes, tumour appearance was significantly accelerated and, in contrast to neuT-only animals, metastases were observed in the lung. These results implicate EphB4 in the regulation of tissue architecture, cellular growth response and establishment of the invasive phenotype in the adult mammary gland.

scholarly journals A Novel Mechanism of Resistance to Mouse Mammary Tumor Virus Infection

2000 ◽  
Vol 74 (6) ◽  
pp. 2752-2759 ◽  
Author(s):  
Tatyana V. Golovkina
Keyword(s):  
Mammary Gland ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Inbred Mice ◽  
Tumor Development ◽  
Mammary Glands ◽  
Mammary Tissue ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

ABSTRACT Exogenous mouse mammary tumor virus (MMTV) is carried from the gut of suckling pups to the mammary glands by lymphocytes and induces mammary gland tumors. MMTV-induced tumor incidence in inbred mice of different strains ranges from 0 to as high as 100%. For example, mice of the C3H/HeN strain are highly susceptible, whereas mice of the I/LnJ strain are highly resistant. Of the different factors that together determine the susceptibility of mice to development of MMTV-induced mammary tumors, genetic elements play a major role, although very few genes that determine a susceptibility-resistance phenotype have been identified so far. Our data indicate that MMTV fails to infect mammary glands in I/LnJ mice foster nursed on viremic C3H/HeN females, even though the I/LnJ mammary tissue is not refractory to MMTV infection. Lymphocytes from fostered I/LnJ mice contained integrated MMTV proviruses and shed virus but failed to establish infection in the mammary glands of susceptible syngeneic (I × C3H.JK)F1 females. Based on the susceptible-resistant phenotype distribution in N2 females, both MMTV mammary gland infection and mammary gland tumor development in I/LnJ mice are controlled by a single locus.

scholarly journals Role of F-Box Protein βTrcp1 in Mammary Gland Development and Tumorigenesis

2004 ◽  
Vol 24 (18) ◽  
pp. 8184-8194 ◽  
Author(s):  
Yasusei Kudo ◽  
Daniele Guardavaccaro ◽  
Patricia G. Santamaria ◽  
Ryo Koyama-Nasu ◽  
Esther Latres ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Transgenic Mice ◽  
Mammary Gland Development ◽  
Mammary Glands ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Ductal Branching ◽  
F Box Protein ◽  
Gland Development

ABSTRACT The F-box protein βTrcp1 controls the stability of several crucial regulators of proliferation and apoptosis, including certain inhibitors of the NF-κB family of transcription factors. Here we show that mammary glands of βTrcp1−/− female mice display a hypoplastic phenotype, whereas no effects on cell proliferation are observed in other somatic cells. To investigate further the role of βTrcp1 in mammary gland development, we generated transgenic mice expressing human βTrcp1 targeted to epithelial cells under the control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. Compared to controls, MMTV βTrcp1 mammary glands display an increase in lateral ductal branching and extensive arrays of alveolus-like protuberances. The mammary epithelia of MMTV βTrcp1 mice proliferate more and show increased NF-κB DNA binding activity and higher levels of nuclear NF-κB p65/RelA. In addition, 38% of transgenic mice develop tumors, including mammary, ovarian, and uterine carcinomas. The targeting of βTrcp1 to lymphoid organs produces no effects on these tissues. In summary, our results support the notion that βTrcp1 positively controls the proliferation of breast epithelium and indicate that alteration of βTrcp1 function and expression may contribute to malignant behavior of breast tumors, at least in part through NF-κB transactivation.

The effect of bromocriptine on mammary-gland ultrastructure of hyperprolactinemic rats

1984 ◽  
Vol 42 ◽  
pp. 204-205
Author(s):  
I.C. Murray
Keyword(s):  
Mammary Gland ◽  
Dopamine Agonist ◽  
Alveolar Epithelium ◽  
Mammary Glands ◽  
Female Rats ◽  
Control Group ◽  
Cell Hyperplasia ◽  
Once Daily ◽  
Long Evans

In women, hyperprolactinemia is often due to a prolactin (PRL)-secreting adenoma or PRL cell hyperplasia. RRL excess stimulates the mammary glands and causes proliferation of the alveolar epithelium. Bromocriptine, a dopamine agonist, inhibits PRL secretion and is given to women to treat nonpuerperal galactorrhea. Old female rats have been reported to have PRL cell hyperplasia or adenoma leading to PRL hypersecretion and breast stimulation. Herein, we describe the effect of bromocriptine and consequently the reduction in serum PRL levels on the ultrastructure of rat mammary glands.Female Long-Evans rats, 23 months of age, were divided into control and bromocriptine-treated groups. The control animals were injected subcutaneously once daily with a 10% ethanol vehicle and were later divided into a normoprolactinemic control group with serum PRL levels under 30 ng/ml and a hyperprolactinemic control group with serum PRL levels above 30 ng/ml.

INTERACTIONS OF OESTRONE AND TESTOSTERONE ON MAMMARY GLANDS OF MALE RABBITS

1961 ◽  
Vol 36 (1) ◽  
pp. 141-156 ◽  
Author(s):  
B. Bengtsson ◽  
A. Norgren
Keyword(s):  
Mammary Gland ◽  
Testosterone Propionate ◽  
Mammary Glands ◽  
List Type ◽  
Stunted Growth ◽  
Abnormal Growth ◽  
Growth Reaction ◽  
Extensive Growth ◽  
Higher Doses

ABSTRACT The effect of testosterone and oestrone on the mammary glands of castrated male rabbits was studied. Testosterone propionate was used in daily doses from 0.5 to 80 mg. The doses of oestrone ranged from 0.05 to 25 μg per day. Mammary glands were examined after 14, 28 or 56 days of injections. 1) Testosterone in doses below 20 mg failed to affect the mammary glands. With 40 or 80 mg a distinct, though abnormal growth reaction was consistently obtained. 2) Oestrone in doses lower than 0.5 μg did not stimulate mammary growth. With 0.5 μg and higher doses extensive growth of the mammary glands occurred. Stunted growth and secretion were found in the mammary glands of rabbits injected with 12.5 or 25 μg oestrone. 3) Testosterone in doses of 1 or 5 to 10 mg depressed or abolished the response of the mammary glands to 0.5 μg oestrone. When testosterone, in doses ineffective when given alone, was added to at least 3.125 μg oestrone, the mammary glands developed alveoli. The abnormalities produced by the highest doses of oestrone studied were exaggerated by the addition of testosterone. 4) The observations indicate a complicated interplay between the actions of testosterone and oestrone on the mammary gland of the rabbit. The interactions between testosterone and oestrone are presumably different from those observed between progesterone and oestrone.

EFFECT OF LOCALLY IMPLANTED OESTROGEN ON THE RESPONSE OF THE RAT'S LACTATING MAMMARY GLAND TO OXYTOCIN

1973 ◽  
Vol 73 (4) ◽  
pp. 700-712 ◽  
Author(s):  
J. D. Bruce ◽  
X. Cofre ◽  
V. D. Ramirez
Keyword(s):  
Mammary Gland ◽  
Mammary Glands ◽  
Myoepithelial Cells ◽  
Recording System ◽  
Saline Infusion ◽  
High Dose ◽  
Low Doses ◽  
Milk Ejection ◽  
Lactating Mammary Gland ◽  
Small Rise

ABSTRACT On the day following delivery (day 1 of lactation) one abdominal mammary gland was implanted with oestrogen and the contralateral gland received an empty needle. At 2, 5 or 10 days of lactation the rats were anaesthetized with pentobarbital and the nipples of both abdominal glands were cannulated and their pressures recorded by means of transducers coupled to an amplifier and recording system. The normal mammary glands of 5-day lactating rats responded to very low doses of oxytocin (Syntocinon®, Sandoz) (5× 10−8 mU) with a rhythmic elevation in pressure. However, saline infusion also evoked a small rise in intra-mammary pressure. Earlier (2 days) and later (10 days) in lactation the responses were smaller. Oestrogen decreases significantly the milk ejection response to oxytocin, and the effect was maximal at day 10 of lactation. Histological observations confirmed the diminished reaction of the gland to oxytocin, since the milk was retained in the alveoli of rats bearing a mammary-oestrogen implant. A paradoxical rise in pressure was detected in normal as well as in oestrogen-implanted glands when the lowest dose of oxytocin was injected in lactating rats which had previously received a high dose of oxytocin (50 mU or 500 mU). These results reinforce the hypothesis that oestrogen alters the milk ejection response to oxytocin and that the mechanism is probably related to changes in the contractility of the myoepithelial cells.

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