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PubMed1992

Long term tumorigenicity of a single application of indomethacin or Amuno in adolescent and in adult male Sprague Dawley rats.

200 adolescent (Group I) and 200 adult male Sprague Dawley rats (Group II) were divided into 4 subgroups of 50 animals each. Animals were treated on the 29th (Group I) or 98th day of life (Group II) either with acetone or Amuno carrier in acetone or Amuno on acetone (2.5 mg indomethacin/100 g animal weight in acetone) or with the pure substance indomethacin 2.5 mg/100 g of animal weight in acetone, giving a single application on the shaved dorsal skin. Subsequently the animals remained under observation until their deaths, followed by autopsy and histopathologic examination of several organs. The rats treated with Amuno of indomethacin in the adolescent stage showed lower body weights and a shorter total survival time. The adolescent animals treated with Amuno or indomethacin showed a significantly higher rate of interstitial testicular tumors of the Leydig tumor type, adenomas and adenocarcinomas of the small and large intestine as well as hepatocellular tumors. The total number of neoplasias was higher in the animals treated with Amuno or indomethacin compared to those treated with acetone or carrier with acetone. Application of Amuno or indomethacin also resulted in a higher rate of hyperplasias (sole of foot, lymph nodes, prostate). The impairment of the synthesis of prostaglandins caused by indomethacin apparently results in starting complex pathomechanisms which have effects until the late death of the animals. Adolescent animals were affected more frequently by the application of indomethacin as were already adult animals.

Aging↗
PubMed2001

The pea3 subfamily ets genes are required for HER2/Neu-mediated mammary oncogenesis.

BACKGROUND: The PEA3 Ets transcription factor is overexpressed in the vast majority of human breast tumors and in nearly all of those of the HER2/Neu-positive subclass. PEA3 is also overexpressed in various transgenic mouse models of this disease. Whether PEA3 plays an essential role in HER2/Neu-mediated oncogenesis has heretofore not been addressed. RESULTS: Here, we report that each of the three highly related ets genes of the pea3 subfamily (pea3, er81, and erm) were coordinately overexpressed in mammary tumors of MMTV-neu transgenic mice. Other ets genes normally expressed in the mammary gland were not upregulated in these tumors. Expression of a dominant-negative pea3 transgene under the control of the MMTV promoter in mammary epithelial cells of MMTV-neu transgenic mice dramatically delayed the onset of mammary tumors and reduced the number and size of such tumors in individual mice. Those tumors that arose in bitransgenic mice expressed the MMTV-neu transgene, but not the MMTV-dominant-negative pea3 transgene. CONCLUSIONS: These findings imply that one or more of the PEA3 subfamily Ets proteins or other Ets proteins with related DNA binding specificity play an essential role in Neu-mediated mammary oncogenesis. Hence, agents that inhibit the expression or activity of the PEA3 subfamily proteins may prove efficacious in the treatment of breast cancer.

Animals↗
PubMed2000

Using genetics to probe host-virus interactions; the mouse mammary tumor virus model.

It is clear that there is genetic variation among different individuals in their susceptibility to infection by viruses and other pathogens. Identification of the genes involved in conferring resistance or susceptibility to viral infection will allow us to understand both mechanisms of infection and pathogenesis and to develop reagents for treating or preventing them. Because of the large number of genetically well-characterized inbred mouse strains and the ability to generate targeted germ line mutations, this species is particularly well-suited for such analysis. This review focuses on how the use of genetics to study the retrovirus mouse mammary tumor virus allowed the dissection of both the viral infection pathway and the response of the host to this infection.

Animals↗
PubMed1978

Synthesis of mouse mammary tumor virus ribonucleic acid in isolated nuclei from cultured mammary tumor cells.

Glucocorticoid hormone treatment of GR cells, a cultured line derived from mouse mammary tumor tissue, selectively stimulates the rate of transcription of integrated proviral genes specifying mammary tumor virus (MTV). We have incubated isolated nuclei from these cells under conditions in which all three endogenous RNA polymerases appear to be active. RNA synthesized in vitro is distinguished from preexisting nuclear RNA by labeling the in vitro products with [3H]CTP, and the level of MTV RNA synthesis is measured by molecular hybridization with unlabeled viral DNA. Synthesis requires the addition of nucleoside triphosphates, and is inhibited by actinomycin D. Pretreatment of GR cells with dexamethasone, a synthetic glucocorticoid, has no significant effect on the amount of total RNA synthesis in isolated nuclei. In contrast, synthesis of MTR RNA is stimulated 10-20-fold in nuclei from dexamethasone-treated cells relative to untreated control nuclei; the sensitivity of in vitro viral RNA synthesis to inhibition by alpha-amanitin suggests that it is carried out exclusively by RNA polymerase II. The fraction of total RNA synthesis which is viral specific (about 0.2-0.4% in nuclei from dexamethasone-treated cells and 0.01-0.03% in controls) is similar to that detected in pulse labeled RNA from whole GR cells in culture. Our procedures for labeling and hybridization of RNA appear to avoid artifacts recently noted in other in vitro transcription systems.

Amanitins↗
PubMed1989

Design, synthesis, antineoplastic activity, and chemical properties of bis(carbamate) derivatives of 4,5-bis(hydroxymethyl)imidazole.

A series of bis(carbamate) derivatives of 1,2-substituted 4,5-bis(hydroxymethyl)imidazoles were prepared and evaluated against murine P388 lymphocytic leukemia. Electron-withdrawing substituents at either N-1 or C-2 gave rise to inactive compounds. However, electron-donating substituents gave active compounds and the 2-(methylthio)-1-methyl derivative 2i (carmethizole), as the bis(N-methylcarbamate), was found to be very active. The derivative 2i, referred to by the name carmethizole, was also shown to be active against the MX-1 mammary xenograft, the human amelanotic melanoma cell line (LOX) xenograft, the M5076 sarcoma, and L1210 lymphocytic leukemia. The solution stability, water solubility, pKa, and log P of carmethizole are also reported.

Animals↗
PubMed1999

The comparative pathology of human and mouse mammary glands.

The mouse has emerged as a primary animal model for human breast cancer because the mammary glands of the two species are very similar in structure and function. In this regard the TDLU and LA have similar morphology. The mouse, infected by MMTV, develops "spontaneous" tumors with specific but limited tumor phenotypes. The advent of genetic manipulation has created transgenic mice that develop hyperplasias and tumors morphologically and cytochemically comparable to lesions in humans. Even experienced pathologists have difficulty distinguishing between lesions from the two species, and the morphological similarities support the utility of the mouse model in understanding human breast cancer. In this essay we review our experience with the histopathology of human and mouse mammary disease by comparing the normal gland with hyperplastic, dysplastic and neoplastic lesions of traditional and transgenic origin.

Animals↗
PubMed2003

Early parity significantly elevates mammary tumor incidence in MMTV-c-myc transgenic mice.

Female transgenic mice, in which a murine c-myc gene has been placed under the transcriptional control of the mouse mammary tumor virus long terminal repeat, are prone to developing mammary adenocarcinomas. Owing to the manner in which these mammary tumors develop, it is clear that exogenous expression of the c-myc transgene is necessary to but insufficient for murine mammary tumorigenesis. The genetic background of study mice has been shown to influence the phenotype induced by different transgenes; furthermore, mammary tumor initiation and progression induced by different transgenes has been shown to be susceptible to significant modification with alterations in and mixing of the genetic background of the study mice. We bred MMTV-c-myc transgenic mice onto a mixed genetic background that resulted in a very significant suppression of mammary tumor incidence for parous mice, bred continuously starting at 10 weeks of age. In this paper, we show that mammary tumor incidence is significantly elevated in these mixed background MMTV-c-myc transgenic mice when they are bred continuously, starting at 7 weeks of age. Early breeding of these mice did not influence mammary tumor multiplicity, latency, histopathology, or number of pregnancies at time of tumor development. These results are the first to demonstrate that breeding age influences mammary tumor incidence in MMTV-c-myc transgenic mice. They suggest that mammary gland susceptibility to tumorigenesis, resulting from the expression of c-myc, may vary with glandular development as is seen for chemical carcinogens.

Animals↗
PubMed1976

Relationship between receptor and mammary tumour virus production after stimulation by glucocorticoid.

A short exposure of primary cultures of mouse mammary tumour cells to glucocorticoids results in at least a three-fold stimulation of mammary tumour virus (MTV) production. Specific interaction of glucocorticoids with the cytoplasmic and nuclear receptors can also be demonstrated. The biological potency of various steroids to stimulate MTV is related directly to the retention of the steroid-receptor complex in the nuclei. Progesterone has a high affinity for the cytoplasmic receptor, is not retained by the nuclei and does not stimulate or block the basal level of MTV production. It is, however, quite effective in abolishing the glucocorticoid-mediated stimulation of MTV and thus behaves as an antagonist of glucocorticoid.

Animals↗
PubMedDate not supplied

Androgen regulation of cell proliferation and expression of viral sequences in mouse mammary tumour cells.

The role of steroids in promoting cell proliferation is well established but the molecular mechanisms are not clear. The S115 mouse mammary tumour cell line provides a model system for molecular studies in vitro in that it exhibits in tissue culture both a positive proliferative response to androgens and a change from a transformed phenotype in the presence of androgen to a normal phenotype when androgen is removed. We have considered here the possible involvement of mouse mammary tumour virus (MMTV) in these processes. We have demonstrated the presence in S115 cells of MMTV-related sequences which are transcribed into RNA only in the long-term presence of androgen. Prolonged culture in the absence of androgen, which results in loss of proliferative response to androgen, is accompanied by loss of MMTV-related RNA and increased methylation of MMTV-related sequences.

Animals↗
PubMedDate not supplied

Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15.

Most mammary carcinomas induced in C3H mice by the mouse mammary tumour virus (MMTV) bear a new proviral insertion within a highly conserved locus on chromosome 15 called int-1. A transcriptional unit within this locus is inactive in all tested normal tissues but expressed at low levels in mammary tumours with proviral insertions positioned on either the 5' and 3' sides of the gene. Transcription of the proviruses proceeds away from int-1; thus an indirect mechanism appears to activate expression of this putative oncogene.

Animals↗
PubMedDate not supplied

Activation of cellular gene by mouse mammary tumour virus may occur early in mammary tumour development.

There is now good evidence that the induction of mammary carcinomas by mouse mammary tumour virus (MMTV) involves provirus activation of specific cellular genes. Thus, a high percentage of virally induced tumours contain an acquired MMTV provirus in either of two defined integration regions, termed int-1 and int-2, and provirus insertion is accompanied by expression of specific RNA transcripts from these regions. We show here that in some recurring, pregnancy-dependent mammary tumours provirus integration within int-2 has already occurred at the earliest appearance of the tumour and may therefore represent an important step in the development of neoplasia. As judged by the distribution of the acquired MMTV proviruses, the tumours recurring at any one site represent the same clonal population of cells as the original tumour and remain clonal during cycles of proliferation and regression, including the transition to hormone-independent status. These data suggest that either the expression of the int-2 locus or the function of this putative oncogene must remain responsive to hormones and that some additional event must be responsible for the transition to autonomous growth.

Age Factors↗