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At least 487 records · Page 27Linked to original sources
PubMed1991

Expression of activated oncogenes in the murine mammary gland: transgenic models for human breast cancer.

Breast cancer is the leading cause of death among non-smoking women and thus has been the focus of intensive research. It has been generally accepted that the deregulation of oncogenes or their regulators play a pivotal role in progression of this prevalent disease. For example, amplification and overexpression of a number of oncogenes has been observed in a proportion of primary breast cancer biopsies. More recently, there has also been reports of inactivation tumor suppressor genes in human breast cancer. While there is compelling evidence for a role of these genes in breast cancer tumor progression due to limitations inherent in these studies it is difficult to establish a direct causal association between expression of a certain oncogene and tumor progression. For this reason many groups have employed the transgenic mouse as a model system to directly study effects of oncogene expression in the murine mammary gland. This review will attempt to highlight some of the important lessons and potential applications that have emerged from the study of oncogene expression in the mammary epithelium of transgenic mice. The utility of the transgenic system to assess the transforming potential of oncogenes, to investigate the multi-step nature of malignant progression, and to be used as models for therapeutic intervention will be discussed.

Animals↗
PubMed1989

Activity of the pyrazoloacridines against multidrug-resistant tumor cells.

A series of 2-aminoalkyl-5-nitropyrazolo [3,4,5-kl]acridines (pyrazoloacridines) were tested in vitro against a panel of multidrug-resistant cell lines comprising Adriamycin-resistant P388 leukemia, B16 melanoma, and mammary adenocarcinoma 16c. This new class of anticancer agents, particularly the 9-substituted methoxy derivatives, exhibited significant activity against all of the lines tested. The degree of cross-resistance to these compounds ranged from zero to 8-fold in the 138-fold Adriamycin-resistant P388/ADR line and was greatly diminished in the B16/ADR and 16c/ADR lines. Selected pyrazoloacridines were subsequently tested in vivo against B16 and B16/ADR cells established as solid tumors from the tissue culture line and shown to retain a significant degree of Adriamycin resistance. Whereas the B16/ADR line exhibited 2 logs less net tumor-cell kill than the B16 parent in response to Adriamycin treatment, the resistant tumor was completely sensitive to the pyrazoloacridines tested and proved in some experiments to be collaterally sensitive. The favorable activity of the pyrazoloacridines against these Adriamycin-resistant tumor lines points to the potential efficacy of these compounds against multidrug-resistant tumors encountered clinically.

Acridines↗
PubMed1981

Independence of H-2 and viral antigens on the cell surface and absence of H-2 antigens on murine leukemia virus and mouse mammary tumor virus particles.

By indirect immunoelectron microscopy we tested for the presence of H-2 antigens on murine mammary tumor virus (MMTV) and murine leukemia virus (MuLV) particles. The association of H-2 antigens and viral antigens on the virus-infected cell surface was investigated with antibody-induced redistribution. Mammary tumor cells and leukemia cell lines with different H-2 genotypes and carrying different MuMTV or MuLV were used. No H-2 antigens could be demonstrated on the envelope of MMTV and MuLV particles, even after the permeabilization of their envelopes with saponin. On the surface of virus-infected cells antibody-induced patching or capping of the viral antigens did not result in copatching or cocapping of the H-2 antigens. In the reciprocal tests no co-redistribution of viral antigens with H-2 antigens was seen. Our experiments failed to show any physical association between H-2 antigens and MMTV or MuLV antigens on the cell surface.

Animals↗
PubMed1985

Proviral unit II of endogenous mouse mammary tumour virus is selectively amplified and expressed in C57B1/10 mammary tumours induced by non-viral carcinogens.

Restriction enzyme analysis and molecular hybridization assay of DNA isolated from C57B1/10 mammary adenocarcinomas induced by a combination of dimethylbenzanthracene, oestrogen, and prolactin, revealed the presence of four extra copies of endogenous mouse mammary tumour virus (MMTV). PstI restriction pattern of the amplified proviral sequences indicated their identity with the proviral Unit II of endogenous MMTV. The amplified proviruses are hypomethylated and expressed in a hormone-dependent fashion. Their internal structure is slightly modified, since an additional EcoRI recognition site is present within the proviral genomic DNA. Selective amplification of Unit II MMTV provirus in the course of mammary tumourigenesis initiated by chemical carcinogens and hormones is compatible with the accepted multifactorial nature of this process, and is interpreted in terms of the insertional mutagenesis model for MMTV-induced oncogenesis. However, sequences of cellular DNA, adjacent to the amplified Unit II proviruses, show no homology to the integration domains int-1 and int-2 common to exogenous MMTV.

Adenocarcinoma↗
PubMed1983

The correlation between tissue differentiation and production of mammary tumor virus (MTV) in transplanted murine mammary tumors. Electron microscopic observations.

The spontaneous mammary tumors of the NMRI mouse are well developed microcystic adenocarcinomas. Serial isologous transplantation of the tumors results in nearly complete dedifferentiation to a solid tumor, in which only electron-microscopically rudimentary acinus-like microlumina can be observed. The adenocarcinomas produce A and B particles in abundance, with the A particles appearing intracellularly in the adluminal cytoplasmic regions of the epithelial cells in association with typical cellular structures and the B particles being restricted to closed extracellular compartments such as vacuoles or acini alone. The loss of alveolar organization in the solid tumors is followed by an almost complete reduction in mature B particles, while A particles are still regularly observed and appear to be less reduced in number. This suggests that the production of extracellular B particles is dependent upon the secretory activity of the tumor cells and that in nonsecreting cells it is predominantly a late step in virus release that is inhibited, not the synthesis of intracellular precursors.

Adenocarcinoma↗
PubMed1982

Role of natural prostaglandins in the control of murine mammary tumor virus expression.

The regulation of murine mammary tumor virus (MuMTV) production by mammotropic hormones, hormonomimetic substances, and cyclic nucleotides was investigated. The virus produced in control and treated mammary tumor cell cultures was quantitated by measuring the supernatant reverse transcriptase activity in exogenous reaction using poly(rC).oligo(dG) as template-primer. Two days after exposure, the synthetic glucocorticoid, dexamethasone (DXMT), increased spontaneous MuMTV production at optimal concentration (0.1 mumol) up to ten times. Dibutyryl derivative of cyclic AMP had no effect on spontaneous MuMTV production, whereas the drug potentiated suboptimal concentrations of the glucocorticoid. Natural prostaglandins, potent agonists of adenylate cyclase catalyzing intracellular synthesis of cyclic AMP, enhanced both basal (up to five times) and DXMT-stimulated (up to 1.6 times) MuMTV replication. The MuMTV-stimulating activity of prostaglandins decreased in the order of PGA1 greater than PGE1 greater than PGB1 greater than PGF2 alpha. Prostaglandins can be replaced partially by norepinephrine and isoproterenol by enhancing the DXMT-mediated MuMTV stimulation, whereas these drugs remained without effect on spontaneous MuMTV production. Theophylline, an antagonist of cAMP-phosphodiesterase converting cAMP to AMP, enhanced the virus-stimulating activity of DXMT as well as of prostaglandins. The enhancement of MuMTV production by adenylate cyclase agonists do not correlate absolutely with the estimates of intracellular cAMP levels, since the highest amounts of cAMP has been repeatedly observed in cells treated with PGE1 and norepinephrine. The results indicate that besides hormones, other hormone-like substances and cyclic nucleotides may be involved in the complex mechanism of hormone-regulated MuMTV genome expression.

Adenocarcinoma↗
PubMed1987

Silver enhancement of protein A-gold probes on resin-embedded ultrathin sections. An electron microscopic localization of mouse mammary tumor virus (MMTV) antigens.

A simple method is described allowing the enhancement of the visibility of small gold probes for the electron microscopy. This method, which allows the silver intensification of gold directly on epon-embedded ultrathin sections, was used for the electron microscopic localization of Mouse Mammary Tumor Virus (MMTV) antigens in cultured cells derived from GR and BALB/cfRIII mouse mammary tumors. After the immunostaining with the preembedding protein A-gold technique, the ultrathin sections, placed on 200 mesh copper grids, were rehydrated and exposed to a photographic developer containing silver nitrate. During this physical development gold particles are incapsulated in growing shells of metallic silver, which gradually become more and more visible. We were able to obtain a heavy labelling of the viral particles, well visible even at low magnification, with a negligeable background staining. The present technique can be useful whenever it is necessary to use the smallest gold probes today available.

Animals↗
PubMed1994

Chemoprevention of mammary tumor virus-induced and chemical carcinogen-induced rodent mammary tumors by natural plant products.

The natural plant products turmeric, beta-carotene, catechin, and betel leaf extract were evaluated for their antitumor effects on mammary tumorigenesis in murine mammary tumor expressing C3H (Jax) mice and in Wistar rats treated with the chemical carcinogen 7-12-dimethylbenz(a)anthracene (DMBA). Administration of turmeric through the diet and of beta-carotene, catechin, and betel leaf extract through the drinking water to virgin female C3H mice resulted in decreased tumor incidence and tumor burden. Administering 5% turmeric in the diet from 2 months of age showed suppression of mammary tumor virus-related reverse transcriptase activity and of preneoplastic changes in the mammary glands. Furthermore, feeding turmeric from 6 months of age resulted in a 100% inhibition of mammary tumors. In the DMBA model of rat mammary tumorigenesis, administration of turmeric, catechin, and betel leaf extract resulted in decreased tumor burden and tumor incidence, and a delay in the onset of mammary tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Sequence determination of the 3' end of mouse mammary tumor virus RNA.

70S RNA has been prepared from mouse mammary tumor virus (MMTV) produced by the GR tumor cell line. After denaturation for 3 min at 60 degrees C the RNA was applied to a sucrose gradient and molecules sedimenting between 10-16S were selected and passed over an oligo-dT cellulose column. The poly A containing RNA fraction was used as a template for the synthesis of complementary DNA with reverse transcriptase in the presence of dideoxynucleoside triphosphates. Oligo-nucleotides p(dT)7rG, p(dT)7rA and (p(dT)7rC were tested for their primer activity. Two of the three primers gave readable sequences. This suggests a heterogeneity in the 3' end of the viral RNA, a phenomenon also observed with avian retroviruses. Nucleotides 37-45 from the 3' end are made up of only A's and T's and resemble a Hogness box. This finding could have biological consequences for the transcription of proviral DNA in the unintegrated and integrated state. Instead of the usual AAUAAA sequence present in mRNA's close and in front of the site of polyadenylation we find a sequence AGUAAA.

Animals↗
PubMed1985

Natural infection of Swiss mice with mouse mammary tumor virus (MMTV): viral expression in milk and transmission of infection.

Quantitative determinations of gp52, the main envelope glycoprotein, and p28, the main core protein, of MMTV, have been performed in about 1000 individual samples of milk of breeding females from our colony of MMTV-infected Swiss mice, a line characterized by a moderate incidence of mammary tumors. A computer analysis of the results showed: 1-- an important individual variation, ranging from 0 to 120 micrograms per ml of milk for p28, and from 0 to 320 micrograms per ml of milk for gp52; 2-- a variation of the release of both antigens during a single lactation, with a maximum on the 7--8th day of nursing; 3-- an increase of the release of both antigens with parity up to the 6th lactation, followed by a marked decrease during later lactations; 4-- a higher degree of infection in the offspring of 2nd and 3rd litters. The possible dependence of viral expression and transmission of infection upon factors such as cyclic activity of the mammary gland and progressive immunization of mice against MMTV is analyzed. The status of our laboratory line of MMTV infected Swiss mice is discussed in comparison with high and low tumor incidence strains.

Animals↗
PubMed1995

Bispecific antibodies retarget murine T cell cytotoxicity against syngeneic breast cancer in vitro and in vivo.

Bispecific antibodies with specificity for CD3 and a tumor antigen can redirect cytolytic T cells to kill tumor targets, regardless of their natural specificity. To assess the clinical potential of bispecific antibodies for treatment of human cancers we have, in the present study, adapted a totally synergeic mouse model to the targeting of mouse T cells against mouse tumors in immunocompetent mice. We show that gp52 of the mouse mammary tumor virus (MTV) can serve as a tumor-specific antigen for redirected cellular cytotoxicity. Chemically crosslinked and genetically engineered bispecific antibodies with specificities for gp52 and murine CD3 epsilon-chain induced activated mouse T cells to specifically lyse mouse mammary tumor cells from cultured lines and primary tumors from C3H-MTV+ mice. Retargeted T cells also blocked the growth of mammary tumors in vitro as well as their growth in syngeneic mice. These findings identify murine MTV-induced mammary adenocarcinomas as a solid-tumor, animal model for retargeting T cells with bispecific antibodies against syngeneic breast cancer.

Adenocarcinoma↗