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At least 469 records · Page 26Linked to original sources
PubMed1989

Spontaneous progression of hyperplastic outgrowths of the D1 lineage to mammary tumors: expression of mouse mammary tumor virus and cellular proto-oncogenes.

Mammary cancer in mice is characterized by progression through defined stages of preneoplasia, with the most common preneoplastic stage being the hyperplastic alveolar nodule (HAN). We determined the relative levels of RNA expression of various cellular proto-oncogenes and endogenous mouse mammary tumor virus genes in outgrowths and tumors of three sublines of the transplantable D1 HAN preneoplastic outgrowth line. The three sublines differed in relative tumor-producing capabilities. Subline D1B produced a high incidence of tumors with short latency periods, whereas sublines D1C and D1D produced low incidences of tumors with long latency periods. No consistent alteration in proto-oncogene expression correlated with relative tumorigenicity, although tumors frequently contained higher levels of one or more proto-oncogene transcripts as compared with preneoplastic tissue. Slightly elevated (2- to 6-fold) levels of different oncogene transcripts were detected in 13 of 17 tumors as compared with outgrowth tissue, including abl (2 tumors), fps (5 tumors), Ha-ras (6 tumors), and Ki-ras (8 tumors). One tumor contained 45 times more Ki-ras-specific RNA than outgrowth tissue because of a comparable amplification of Ki-ras DNA sequences. Elevated levels of Ha-ras occurred more frequently in tumors of a high-incidence subline than in a less-aggressive subline (5/10 vs 1/7), but this difference was not statistically significant. However, consistent changes in MMTV expression accompanied progression from preneoplastic tissues to mammary tumors. All 17 tumors displayed reduced levels of the MMTV-specific long terminal repeat (LTR) transcript (1.6 kb) as compared with HAN tissue; tumors with moderate levels of LTR transcript expressed the 3.8-kb envelope message as well, one not detected in HANs. Expression of the LTR transcript is apparently influenced by factors in addition to the methylation status of endogenous mouse mammary tumor virus genes, which was similar in outgrowths and tumors. As the survey of representative proto-oncogenes failed to identify a uniform change between HAN and tumors, it is likely that other genes are involved in tumor progression in the mammary gland.

Animals↗
PubMed1994

Potentiation of glucocorticoid-mediated induction of the mouse mammary tumor virus promoter in mammary carcinoma cells by activation of protein kinase C.

In a mammary carcinoma cell line, the glucocorticoid induction of a stably integrated mouse mammary tumor virus-luciferase reporter gene is potentiated up to ten-fold by treatment of the cells with phorbol ester tumor promoters. This potentiation is stereospecific and is observed with a structurally unrelated tumor promoter that also activates protein kinase C. Another tumor promoter, thapsigargin, that acts via mobilization of intracellular calcium stores, fails to potentiate the hormone response. This potentiation contrasts to the inhibition or lack of effect observed in fibroblasts. Cell specific interactions of different signal transduction pathways with steroid response pathways may play an important role in determining the tissue specificity of steroid hormone action.

Animals↗
PubMed1994

Antizyme delays the restoration by spermine of growth of polyamine-deficient cells through its negative regulation of polyamine transport.

Effects of antizyme on polyamine transport and spermine restoration of the growth of polyamine-deficient cells were examined by using mouse FM3A cells transfected with pMAMneoZ1 possessing rat antizyme cDNA under the control of glucocorticoid-inducible promoter. Treatments of the transfected cells with alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and dexamethasone, an inducer of antizyme, both caused a decrease in ODC activity and polyamine contents and inhibition of cell growth. However, spermine uptake of the transfected cells was repressed by dexamethasone but stimulated by DFMO. The decrease in the rate of spermine uptake in dexamethasone-treated cells was attributed to an increase in Km value and a slight decrease in Vmax value. Accordingly, restoration of cell growth by spermine was less effective in dexamethasone-treated cells than DFMO-treated cells. These results clearly indicate that antizyme has dual functions: one for ODC degradation and the other for negative regulation of polyamine transport.

Animals↗
PubMed2001

Cooperating oncogenic events in murine mammary tumorigenesis: assessment of ErbB2, mutant p53, and mouse mammary tumor virus.

We are investigating cooperating genetic events in the genesis of breast cancer, using the mouse as a model system. We have shown cooperativity between a mutant allele of p53 (p53-172H) and overexpressed ErbB2 in mammary tumorigenesis in transgenic mice. We are now performing additional crosses to further examine oncogene cooperativity with ErbB2 and p53-172H. We attempted to test the dominant oncogenic potential of p53-172H in an in vivo setting by crossing the p53-172H transgene together with ErbB2 onto either a p53(-/-) or a p53(+/-) background. We show that the p53-172H allele and the heterozygous p53 genotype have an identical impact on the latency of ErbB2-induced mammary tumors; there was no evidence of additivity or synergy between p53-172H and the p53(+/-) genotype. On the p53(-/-) background, we obtained no mammary tumors due to the early onset of lymphomas and sarcomas, thus precluding assessment of the effect of the p53-172H transgene on mammary tumorigenesis in a p53-null background. Thus, in this in vivo model for breast cancer, we failed to find evidence that p53-172H can function as a dominant oncogenic allele, but rather found support for its being essentially equivalent to a null allele in its impact on ErbB2-induced mammary tumorigenesis. By comparative genome analysis, we showed that a common feature of tumors arising in ErbB2/mutant p53 mice (p53-null allele with or without p53-172H) is a loss of chromosome 4, a feature of many epithelial tumors in mice and one that is consistent with a role for loss of INK4a/ARF in such tumors. We also attempted to accelerate ErbB2-induced mammary tumorigenesis with mouse mammary tumor virus (MMTV) proviral tagging mutagenesis, but we were surprised to find that mice with MMTV alone had the same latency as mice with both MMTV and ErbB2, indicating no cooperativity between ErbB2 and MMTV. This may have been due to the mixed C3H/HeN x FVB strain background used in this cross.

Alleles↗
PubMed1995

Chronic toxicity/oncogenicity of dimethylacetamide in rats and mice following inhalation exposure.

The potential chronic toxicity and oncogenicity of dimethylacetamide (DMAC) was evaluated by exposing male and female rats and mice to 0, 25, 100, or 350 ppm DMAC for 6 hr/day, 5 days/week for 18 months (mice) or 2 years (rats). Clinical pathology was evaluated at 3, 6, 12, 18, and 24 (rats only) months. An interim euthanization for rats occurred at 12 months and hepatic cell proliferation in rats and mice was examined at 2 weeks and 3 and 12 months. No compound-related effects on survival were observed. Rats exposed to 350 ppm had lower body weight and/or body weight gain. There were no compound-related effects on body weight or weight gain in mice at any concentration. There were no compound-related adverse effects on the incidence of clinical signs of toxicity in rats or mice. No hematologic changes were observed in either species. Serum sorbitol dehydrogenase activity was increased in rats exposed to 350 ppm. Serum cholesterol and glucose concentrations were significantly higher in 100 and 350 ppm female rats. Compound-related morphological changes were observed in the liver. In rats, exposure to 100 or 350 ppm produced increased absolute and/or relative liver weights, hepatic focal cystic degeneration, hepatic peliosis, biliary hyperplasia (350 ppm only), and lipofuscin/hemosiderin accumulation in Kupffer cells. In mice, exposure to 100 or 350 ppm produced increased absolute and relative liver weights (350 ppm females only), accumulation lipofuscin/hemosiderin in Kupffer cells, and centrilobular single cell necrosis. Male rats exposed to 350 ppm also had significantly higher absolute and relative kidney weights which correlated with the gross and microscopic changes resulting from a compound-related increase in severity of chronic progressive nephropathy. Female mice exposed to 350 ppm had an increased incidence of bilateral, diffuse retinal atrophy. No increase in hepatic cell proliferation was seen in mice or rats at any exposure concentration. DMAC was not oncogenic under these experimental conditions in either the rat or mouse. The NOAEL for male and female rats and mice is 25 ppm.

Acetamides↗
PubMed1995

The chromosomal location of the mouse mammary tumor gene Int6 and related pseudogenes in the mouse genome.

The Int6 gene is a common insertion site for the mouse mammary tumor virus (MMTV) in mouse mammary tumors. We have determined that this gene is located centromeric of the Myc protooncogene on mouse chromosome 15. In the mouse genome there are several other Int6-reactive restriction fragments that are located on mouse chromosomes 6, 11, 14, 17, and 18. Nucleotide sequence analysis of four of six of these additional Int6 fragments showed that they contain processed Int6 pseudogenes. Comparisons between the Int6 genes of the inbred mouse laboratory strains and the wild mouse species Mus spretus and Mus mus musculus indicate that some pseudogenes were present before divergence of these species and others were acquired since their separation.

Animals↗
PubMed1995

Oncogene activation and oncogene cooperation in MMTV-induced mouse mammary cancer.

In this short review, we will give an overview of the various genes that can be activated by insertion of proviral DNA of the mouse mammary tumor virus during the formation of mammary cancer. These genes fall within three families: Wnt genes, FGF genes and Notch-related genes. We will summarize our current understanding of the roles of these genes in tumorigenesis and in normal development, and the mechanisms of action of their gene products. Finally, we will give some examples of cooperation between these genes in various biological settings.

Animals↗
PubMed1995

Expression of the mouse mammary tumor virus long terminal repeat open reading frame promotes tumorigenic potential of hyperplastic mouse mammary epithelial cells.

The retrovirus mouse mammary tumor virus (MMTV) 3' long terminal repeat (LTR) contains an open reading frame (ORF) for a 36-kDa protein and encodes a superantigen activity [pORF(sag)]. We have tested the potential oncogenic activity of pORF(sag) in two immortalized mouse mammary epithelial cells. We subcloned MMTV LTR ORF DNA into the pRc/CMV mammalian expression vector in order to place LTR ORF transcription under the control of the constitutive CMV promoter. Mouse mammary epithelial cell lines TM3 and FSK7e4 were transfected and G418-resistant cell clones were isolated. Reverse transcription-polymerase chain reaction and Northern blot analyses revealed modest overexpression of LTR RNA in several transfected cell clones of each line. Individual cell clones were transplanted into cleared mammary gland fat pads of syngeneic BALB/c mice. The parental cell lines and FSK7e4-derived clones did not form tumors, whereas ORF-transfected clones derived from the TM3 cells formed tumors within 8 weeks in 100% of transplanted fat pads in multiple experiments. The tumor cells expressed exogenous LTR ORF RNA and were proven to be derivatives of TM3 cells based on a marker p53 mutation. Immunohistochemistry using a polyclonal antiserum raised against pORF(sag) expressed in insect cells revealed a cytoplasmic reaction in TM3-CMV-LTR tumor cells; a much weaker cytoplasmic reaction was detected in the transfected tissue culture cells. These observations suggest that MMTV pORF(sag) may act as an oncogene in certain mouse mammary epithelial cells and raise the possibility that pORF(sag) may have a role in mammary tumorigenesis. As the parental FSK7 cell line has produced only ductal outgrowths upon transplantation in vivo and the TM3 cell line produces a nontumorigenic hyperplasia, the results suggest further that pORF(sag) may influence the latter stages of mammary tumorigenesis, namely, the preneoplastic to neoplastic transformation.

Animals↗
PubMed1999

Expression of mouse mammary tumor virus envelope protein does not prevent superinfection in vivo or in vitro.

Inbred mice expressing endogenous mouse mammary tumor virus envelope proteins can be infected with exogenous virus, and the mammary tumors that develop in these mice usually have many proviruses integrated in their genomes, indicating that this virus is not subject to receptor interference. We show here that transgenic mice expressing an exogenous mouse mammary tumor virus (C3H) envelope protein can still be infected with this virus. Moreover, cultured mammary gland cells expressing the mouse mammary tumor virus (C3H) envelope protein can be superinfected with pseudotyped viruses bearing that same protein. Thus cellular expression of the mouse mammary tumor virus envelope protein does not block superinfection in vivo or in vitro.

Animals↗
PubMed1995

Dietary effects on gene expression in mammary tumorigenesis.

Studies were undertaken to determine the effect a high fat diet has on the hormonally controlled transcription of the Mtv-1 locus in C3Hf mice. The expression of this locus in the initiating event in mammary tumor development in the C3Hf mouse. Mice were weaned at 21 days to either a high fat diet containing 23.5 percent corn oil or to a low fat diet containing 5 percent corn oil. Mice were sacrificed at first, second, and third parity, or when they had developed mammary tumors, and their mammary glands and mammary tumors were isolated. RNA was isolated from all mammary glands and breast tumors and analyzed. The high fat diet accelerated the transcription of the Mtv-1 locus. The transcripts of this locus, which are never seen in C3Hf mouse mammary glands until second parity, were present in first parity mammary glands of 6 out of 10 high fat diet C3Hf mice which were studied. The mammary glands of 15 first parity C3Hf mice which were on the low fat diet were analyzed and none contained the Mtv-1 specific transcripts. In addition, mammary tumor development was detected earlier (11 vs 17.8 months) and after fewer litters (2.1 vs. 4.2) on the average in high fat diet C3Hf mice. One C3Hf mouse on the high fat diet developed a breast tumor at six months without going through pregnancy. These results indicate that a high fat diet of 23.5 percent corn oil can accelerate hormonally controlled gene expression specifically linked to mammary tumorigenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗