The SV40 T‐antigen induces premature apoptotic mammary gland involution during late pregnancy in transgenic mice

Tzeng, Yin-Jeh; Gottlob, Katrin; Santarelli, Roberta; Graessmann, A.

doi:10.1016/0014-5793(96)00021-x

Cited by 13 publications

(7 citation statements)

References 16 publications

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“…18 ± 20 Premature apoptosis during pregnancy in mice carrying a Simian virus 40 T antigen (SV40 Tag) transgene was associated with a steady level of Bax expression. 21,22 Loss of functional Bax reduced apoptosis by 20% in the first stage of mouse mammary involution. 23 Participation of ICE in mammary cell apoptosis has also been suggested in previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the surviving cells underwent deregulated growth and resulted in tumor formation after the first pregnancy. 21,22 As well, Bcl-2 was shown to be anti-proliferative in addition to its anti-apoptotic function. 46 In our study, the decrease of Bcl-2 expression at 24 h postinfection may in part account for the increased rate of cell proliferation.…”

Section: Cell Death and Differentiationmentioning

confidence: 99%

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Escherichia coli induces apoptosis and proliferation of mammary cells

Long

Capuco²,

Wood³

et al. 2001

Cell Death Differ

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Mammary cell apoptosis and proliferation were assessed after injection of Escherichia coli into the left mammary quarters of six cows. Bacteriological analysis of foremilk samples revealed coliform infection in the injected quarters of four cows. Milk somatic cell counts increased in these quarters and peaked at 24 h after bacterial injection. Body temperature also increased, peaking at 12 h postinjection. The number of apoptotic cells was significantly higher in the mastitic tissue than in the uninfected control. Expression of Bax and interleukin-1b converting enzyme increased in the mastitic tissue at 24 h and 72 h postinfection, whereas Bcl-2 expression decreased at 24 h but did not differ significantly from the control at 72 h postinfection. Induction of matrix metalloproteinase-9, stromelysin-1 and urokinase-type plasminogen activator was also observed in the mastitic tissue. Moreover, cell proliferation increased in the infected tissue. These results demonstrate that Escherichia coli-induced mastitis promotes apoptosis and cell proliferation. Cell Death and Differentiation (2001) 8, 808 ± 816.

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Section: Discussionmentioning

confidence: 99%

Section: Cell Death and Differentiationmentioning

confidence: 99%

Escherichia coli induces apoptosis and proliferation of mammary cells

Long

Capuco²,

Wood³

et al. 2001

Cell Death Differ

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“…The process of tumorigenesis is marked by a competition between proliferation and apoptosis. When TAg is expressed during the ®rst pregnancy it triggers both cell proliferation and p53-independent apoptosis ( Figure 1a) (Li et al, 1996a;Tzeng et al, 1996). The rate of cell proliferation remains relatively high throughout tumorigenesis, but the incidence of apoptosis falls as the cells transition to hyperplasia and adenocarcinoma (Furth et al, 1999).…”

Section: In the Wap-tag Mouse Model Of Breast Cancer Carcinogenesis mentioning

confidence: 99%

WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis

Lewis

Capuco

et al. 2000

Oncogene

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Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth and death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell ± cell signaling, and extracellular matrix. Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at dierent stages of tumorigenesis, and to test the strength of speci®c interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the Simian Virus 40 T antigen (TAg). TAg expression is triggered by hormonal stimulation, either during estrus or pregnancy. Breast adenocarcinomas (ranging from well to poorly dierentiated) develop in 100% of the female mice by approximately 8 ± 9 months of age. Three distinct stages of tumorigenesis are easily identi®ed: an initial proliferation, hyperplasia, and adenocarcinoma. The mean time to ®rst palpable tumor in mice which undergo at least one pregnancy is 6 months. The tumorigenic process is marked by a competition between proliferation and apoptosis and is characterized by cellular acquisition of genetic mutations and increased stromal ®brosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in these adenocarcinomas. c-Fos protein levels are slightly increased in these cancers, while c-Jun levels do not change. Hormonal exposure alters progression. Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transient hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance also can be accelerated through over expression of the cell survival protein, Bcl-2. Bcl-2 over expression not only reduces apoptosis during the initial proliferative process but also decreases the total rate of cell proliferation. This block in cell proliferation is lost selectively as the cells transition to adenocarcinoma. The WAP-TAg model can be utilized to investigate how the basic processes of cell proliferation, apoptosis, DNA mutation, and DNA repair are modi®ed by external and internal signals during mammary oncogenesis.

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“…As a consequence the animals are`milk-less'. Apoptotic cell death is indicated by distinct morphological alterations such as nuclear condensation and shedding of the cells into the alveolar and ductal lumen; it is further demonstrable by TUNEL or Hoechst dye 33258 staining (Tzeng et al, 1996) and spontaneous DNA fragmentation which continues until the third day of the lactation period (Figure 1c). At day 3 ± 4 of lactation, the morphology of the glands resembles that of virgin animals.…”

Section: Sv40 T/t-antigen Induces Premature Mammary Gland Involution mentioning

confidence: 99%

“…As one consequence of the T/t-antigen synthesis all females have a reduced lactation capacity and the o spring have to be nursed by foster mothers (Tzeng et al, 1993). The reason for this`milk-less' phenomenon is a premature mammary gland involution, which occurs during late pregnancy when about 70 ± 80% of the mammary glands epithelial cells are eliminated by apoptosis (Tzeng et al, 1996). However, after lactation the mammary glands still contain multiple SV40 T-antigen positive cell islands which in time expand and develop into breast tumors after the ®rst lactation period (Santarelli et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

SV40 T/t-antigen induces premature mammary gland involution by apoptosis and selects for p53 missense mutation in mammary tumors

et al. 1998

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We recently established transgenic animals (WAP-SV-T/ t) carrying the early coding region of Simian Virus 40 (SV40) under the transcriptional control of the whey acidic milk protein promoter (WAP), which restricts the expression of the transgene to mammary gland epithelial cells (ME-cells). SV40 T/t-antigen synthesis causes premature mammary gland involution during late pregnancy by inducing apoptosis and leads to development of mammary tumors after the ®rst lactation period in both p53 positive (WAP-SV-T/t) and p53 negative double transgenic animals (WAP-SV-T/t.p537/7). The high apoptotic rate persists in all of the T/t-antigen positive breast tumor cells, as well as in established MEtissue culture cell lines. ME-cells which spontaneously switch o the expression of the WAP-SV-T/t transgene do not undergo apoptosis. However, these cells again exhibit an extensive DNA fragmentation when SV40 T/ t-antigen synthesis is reintroduced, which indicates that it is the expression of T/t antigen which is the critical factor for induction of apoptosis. In addition, we isolated several ME-cell lines from di erent breast tumors which have spontaneously lost the T/t-antigen yet remain maximally transformed. Strikingly, these cells contain a missense mutation of the p53 gene at codon 242 (p53 242 ), which substitutes alanine for glycine. This mutation increases p53 stability and it reduces the transactivating function of p53, albeit without a ecting the ability of the protein to interact with the DNA. This indicates that p53 missense mutations are selected for in breast tumors initially expressing T/t-antigen. Therefore, the p53 242 mutation is su cient to maintain the transformed state after the ME-cells have switched o the WAP-SV-T/t transgene. Interestingly, the p53 minus state per se is not su cient to induce ME-cell transformation since homozygous null mice for the p53 gene (p537/7) fail to develop breast cancer.

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The SV40 T‐antigen induces premature apoptotic mammary gland involution during late pregnancy in transgenic mice

Cited by 13 publications

References 16 publications

Escherichia coli induces apoptosis and proliferation of mammary cells

Escherichia coli induces apoptosis and proliferation of mammary cells

WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis

SV40 T/t-antigen induces premature mammary gland involution by apoptosis and selects for p53 missense mutation in mammary tumors

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