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PubMed1975

Sulfhydryl dependence in primary explant hematopoietic cells. Inhibition of growth in vitro with vitamin B12 compounds.

Primary explants of P388, EL-4, and L1210 murine leukemia cells and of normal mouse bone marrow are shown to require sulfhydryl compounds for proliferation in vitro. Nine extablished cell lines show no stimulation by these compounds. Leukemia cells can lose the sulfhydryl dependence after various periods of adaptation to in vitro culture. Various sulfhydryl compounds have widely differing potencies in promoting in vitro proliferation of dependent cells. The effect appears to be specific for sulfhydryl groups in the reduced form. Vitamin B12 compounds inhibit the growth of sulfhydryl-requiring cells, apparently by catalyzing the oxidation of the sulfhydryl groups.

Animals↗

PubMed1978

Isolation of host-range variants of mouse mammary tumor viruses that efficiently infect cells in vitro.

Host-range variants of mouse mammary tumor virus (MMTV) have been isolated that have the ability to productively infect cells in vitro with high efficiency (at multiplicities of infection </=1) and with extremely short latent periods to the production of de novo virus (as short as 4 days after infection). These variants of the highly oncogenic MMTV of RIII, C3H, and GR mice were obtained by serial virus passage in feline cells. The resultant variant stocks react in group-specific radioimmunoassays for the MMTV major external glycoprotein (gp52) and major internal protein (p28), possess a protein profile similar to that of wild-type MMTV, and contain a virion-associated DNA polymerase with a magnesium cation preference. Addition of dexamethasone and insulin to culture media enhances the titer of de novo MMTV to levels of approximately 10(10) particles per 75-cm(2) flask (containing 5 x 10(6) cells) per 24 hr. Variant stocks exhibit no evidence of contamination with either murine or feline type C retroviruses, as assayed by various techniques. The variants of MMTV derived from C3H and RIII mice exhibit differential host ranges that include the ability to productively infect feline, canine, bat, mink, murine, and human cells. Use of these MMTV host-range variants now facilitates the study of the complete replicative cycle of MMTV as well as an elucidation of the interaction of MMTV with various hormones, physical or chemical carcinogens, and tumor promoters in the initiation and promotion of mammary neoplasia.

Animals↗

PubMed1978

Differential expression of poly(A)-adjacent sequences of mammary tumor virus RNA in murine mammary cells.

Two DNA probes representative of either the entire mouse mammary tumor virus (MMTV) genome or the poly(A)-adjacent sequences at the 3' end of MMTV RNA were synthesized with calf thymus DNA or oligo(dT) primers, respectively. These probes were used to study the expression of endogenous MMTV sequences in several BALB/c mammary tumor cell lines, in normal lactating BALB/c tissue, and in a cloned C3H tumor cell line. Both probes were characterized with respect to their rates of hybridization with template RNA, their size as determined by alkaline sucrose gradient centrifugation, and the thermal stability of the cDNA.MMTV RNA hybrids. In addition, the ability of the calf thymus oligodeoxy-nucleotide- or oligo(dT)-primed probes to protect (125)I-labeled MMTV RNA or (125)I-labeled poly(A)-adjacent MMTV RNA sequences from S1 nuclease digestion was determined. Hybridization analysis with these two probes indicated that (i) there were approximately 20-fold more oligo(dT)-primed sequences in BALB/c lactating tissue than there were sequences representing the entire genome; (ii) in BALB/c tumor cells, the oligo(dT):random oligonucleotide-primed cDNA sequence ratio was reduced to 4:1; and (iii) in virus-producer C3H tumor cells, there was only a 2-fold excess of oligo(dT)-primed sequences over that observed with a representative cDNA. These results are consistent with the presence of subgenomic viral mRNA species, integration of partial proviral copies, or altered mRNA processing.

Animals↗

PubMed1978

Identification of the Mtv-2 gene responsible for the early appearance of mammary tumors in the GR mouse by nucleic acid hybridization.

In the mouse strain GR, the Mtv-2 gene controls the expression of large amounts of mammary tumor virus (MTV) antigens in the milk at first lactation. It also controls the early appearance of mammary tumors. We have investigated the number of MTV proviral sequences associated with this Mtv-2 gene by nucleic acid hybridization between MTV [(3)H]cDNA and DNA from GR, B10, and GR-Mtv-2(-) mice. B10 and GR-Mtv-2(-) mice lack Mtv-2 gene expression. The molecular hybridizations revealed that the DNA of GR mice contains 12 copies of MTV proviral sequences, whereas only 4 copies are present in the DNA of B10 and GR-Mtv-2(-) mice. We therefore conclude that the Mtv-2 gene in the GR mouse strain is associated with eight additional MTV proviral sequences. The four Mtv proviral sequences in the GR-Mtv-2(-) DNA might represent another Mtv gene in the GR mouse. Different amounts of MTV RNA are detected in mammary glands at first lactation of B10 and GR-Mtv-2(-) mice, even though both contain four copies of MTV proviral sequences. This indicates a difference between these two mouse strains either in the regulation of expression of these MTV proviral sequences or in the location of these sequences in the murine genome.

Animals↗

PubMed1979

Mouse mammary tumor virus genome expression in chemical carcinogen-induced mammary tumors in low- and high-tumor-incidence mouse strains.

Involvement of mouse mammary tumor virus (MMTV) in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis was investigated in low- (BALB/c) and high- (BALB/cfC3H) mammary-tumor-incidence mouse strains. Both strains contain endogenous MMTV integrated into the cellular genome. Additionally, BALB/cfC3H mice are infected with exogenous MMTV-S which is responsible for a higher incidence of mammary tumors in breeding females. Administration of DMBA to virgin mice of both strains resulted in a moderate frequency of mammary tumors within 40 wk after treatment. No differences were found in DMBA-induced tumor incidences at 18 wk (6% and 7%) or at 38 wk (29% and 36%) after treatment of BALB/c and BALB/cfC3H mice, respectively. Expression of MMTV in these tumors was examined by assaying for the presence of MMTV RNA by hybridization using MMTV-specific cDNA and by immunohistochemical staining utilizing antibodies against MMTV 52,000-dalton glycoprotein, gp52, and 28,000-dalton internal protein, p28. Of 16 BALB/c tumors assayed, 11 did not contain detectable levels of MMTV RNA and the remaining 5 tumors contained only low levels (0.0005-0.0010%) of viral RNA. Importantly, MMTV RNA was not detected in 5 of 27 BALB/cfC3H tumors. The other BALB/cfC3H tumors contained quantities of MMTV RNA ranging from 0.0006 to 0.4170%. Most BALB/cfC3H tumors with detectable levels of MMTV RNA also synthesized viral proteins gp52 and p28. Thus, expression of the complete MMTV genome is not requisite for maintenance of the tumor phenotype in DMBA-induced mammary tumors in either BALB/c or BALB/cfC3H virgin mice under 1 year of age.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1981

Activation of related transforming genes in mouse and human mammary carcinomas.

High molecular weight DNAs of five tumors induced by mouse mammary tumor virus (MMTV), two mouse mammary tumors induced by a chemical carcinogen, and one human mammary tumor cell line (MCF-7) were assayed for the presence of transmissible activated transforming genes by transfection of NIH 3T3 mouse cells. DNAs of all five MMTV-induced tumors, one chemical carcinogen-induced tumor, and the human tumor cell line induced transformation with high efficiencies (approximately 0.2 transformant per micrograms of DNA). NIH cells transformed by DNAs of MMTV-induced tumors did not contain exogenous MMTV DNA sequences, indicating that MMTV-induced mammary carcinomas contained activated cellular transforming genes that were not linked to viral DNA. The transforming activities of DNAs of all five MMTV-induced tumors, the chemical carcinogen-induced mouse tumor, and the human tumor cell line were inactivated by digestion with the restriction endonucleases Pvu II and Sac I, but not by BamHI, EcoRI, HindIII, Kpn I, or Xho I. These results indicate that the same or closely related transforming genes were activated in six different mouse mammary carcinomas, induced by either MMTV or a chemical carcinogen, and in a human mammary carcinoma cell line.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1982

Identification of an antigen associated with transforming genes of human and mouse mammary carcinomas.

Sera from tumor-bearing mice immunoprecipitated a 86,000-dalton glycoprotein from extracts of NIH cells transformed by human mammary carcinoma DNA. This antigen was not immunoprecipitated from extracts of NIH 3T3 cells, spontaneously transformed NIH cells, NIH cells transformed by normal human DNA, NIH cells transformed by human bladder carcinoma DNA, or NIH cells transformed by Rous sarcoma virus DNA. In addition, sera from mice bearing tumors induced by NIH cells transformed by either normal human DNA or human bladder carcinoma DNA did not immunoprecipitate this antigen from extracts of NIH cells transformed by human mammary carcinoma DNA. However, this antigen was immunoprecipitated by sera from mice bearing tumors induced by NIH cells transformed by mouse mammary carcinoma DNAs and from mice bearing primary mammary carcinomas. These results indicate that this glycoprotein represents an antigen that is specifically associated with expression of the transmissible transforming genes of human and mouse mammary carcinomas.

Animals↗

PubMed1982

Low-calorie diet prevents the development of mammary tumors in C3H mice and reduces circulating prolactin level, murine mammary tumor virus expression, and proliferation of mammary alveolar cells.

The effect of carlorie intake on the development of spontaneous mammary tumors in virgin C3H mice was studied. Only about 10% of the mice fed a low-calorie diet [10 kcal/day (1 kcal = 4.184 kJ)] since weaning developed mammary tumors, compared to about 60% of those mice that were reared on high-calorie diets (16 kcal/day or lab chow ad lib). In order to understand the mechanism by which a low-calorie diet decreases the occurrence of mammary tumors in mice, we compared the sex cycle, the amounts of circulating thyroid-stimulating hormone (thyrotropin), growth hormone, and prolactin, the production of type A and B virus particles in the mammary glands, and the morphology of the mammary glands of mice fed low- and high-calorie diets. The amount of serum prolactin and the synthesis of type A and B particles in mammary tissues of mice fed a low-calorie diet was markedly decreased compared to those of age-matched mice fed high-calorie diets. In addition, in young mice fed a low-calorie diet, there were fewer mammary alveolar lesions than in mice fed a high-calorie diet, although the size of the lesions was similar. However, in older mice fed the high-calorie diet, the number and size of these lesions were greater than in the mice raised on the low-calorie diet. The other factors that we studied were not affected by calorie restriction. Our findings suggest that the reduction in serum prolactin level, mammary tumor virus production, and proliferation of mammary alveolar lesions associated with dietary calorie restriction is responsible for lowering the incidence of mammary tumors in mice.

Animals↗

PubMed1984

Expression of an 86-kilodalton glycoprotein in an idiopathic mammary adenocarcinoma of a BALB/c mouse.

An epithelial cell line (BALB/c-ST) was established from a mammary adenocarcinoma that developed spontaneously in a 20-month-old BALB/c mouse. Like uninfected normal tissues, the cell line was found to contain three endogeneous murine mammary tumor virus (MuMTV) proviruses, but MuMTV particles and antigens were not detected. The cultured cells, after being inoculated subcutaneously, produced tumors in syngeneic mice, and sera from a high percentage of the tumor-bearing mice specifically immunoprecipitated an 86-kilodalton antigen from the extracts of BALB/c-ST cells. This antigen was found to be glycosylated, but whether or not it was exposed to the cell surface could not be demonstrated by cell-surface iodination and immunoprecipitation studies. The 86-kilodalton antigen, a glycoprotein designated gp86, was not detected in immunoprecipitates from extracts of normal mammary cells or from the extracts of GR, C3H, and BALB/cfC3H mammary tumor cells. After being infected in vitro with RIII-derived MuMTV but not with C3H-derived MuMTV, the BALB/c-ST cells appeared to undergo a phenotypic change in that they did not produce tumors in syngeneic mice, and the expression of gp86 was inhibited. Our results indicate that the expression of gp86 in the mammary cells of BALB/c mice is a consequence of neoplastic transformation and that MuMTV infection modulates its expression.

Adenocarcinoma↗

PubMed1985

Estradiol 16 alpha-hydroxylation in the mouse correlates with mammary tumor incidence and presence of murine mammary tumor virus: a possible model for the hormonal etiology of breast cancer in humans.

In this report, we describe our findings on the relationship between estradiol 16 alpha-hydroxylation and mammary tumor incidence. A close correlation between the two has been demonstrated with 16-hydroxylation being elevated in strains with a high incidence of tumors, such as RIII and C3H, and low in strains with a low incidence of cancer, such as C57BL. The extent of reaction is highly reproducible and unaffected by age or presence of overt mammary tumors. Studies on the inheritance of estradiol 16 alpha-hydroxylase showed that it is inherited as an autosomal dominant and is not correlated with estradiol 2-hydroxylase or androgen and progestin 16 alpha-hydroxylases. In addition, the reaction was shown to be markedly enhanced by the presence of murine mammary tumor virus and diminished in the absence of the virus. These studies establish a relationship between genetics, hormonal factors, and murine mammary tumor virus, the three key factors in mammary tumorigenesis.

Age Factors↗

PubMed1989

The mouse homolog of the hst/k-FGF gene is adjacent to int-2 and is activated by proviral insertion in some virally induced mammary tumors.

The fibroblast growth factor-related protooncogenes, int-2 and hst/k-FGF, are within 17 kilobase pairs of one another on mouse chromosome 7 and are in the same transcriptional orientation. Approximately 70% of tumors induced in BR6 mice by mouse mammary tumor virus have proviral insertions adjacent to the int-2 gene. We find that the murine homolog of the hst/k-FGF gene can also be transcriptionally activated by the insertion of mouse mammary tumor virus DNA either upstream or downstream of the gene. In most tumors, only one of these adjacent genes is activated, but in some cases both genes are expressed. One of the hst-expressing tumors also has a virally activated int-3 gene. At least five distinct cellular genes (int-1, -2, -3, -4, and hst/k-FGF) can therefore contribute, either singly or in concert, to the development of histologically indistinguishable mammary tumors in mice infected by mouse mammary tumor virus.

Animals↗

PubMed1990

Glucocorticoid receptor-dependent disruption of a specific nucleosome on the mouse mammary tumor virus promoter is prevented by sodium butyrate.

Our laboratory has previously developed cell lines derived from mouse NIH 3T3 fibroblasts and C127 mammary tumor cells that stably express mouse mammary tumor virus (MMTV) long terminal repeat fusion genes in bovine papillomavirus-based episomes. Glucocorticoid hormone strongly activates transcription from episomes and induces the disruption of a single nucleosome in an array of phased nucleosomes on the MMTV promoter. Sodium butyrate inhibits the glucocorticoid hormone-dependent development of a nuclease-hypersensitive site that is due to the displacement of this nucleosome, and inhibits induction of RNA transcripts from episomes. Saturation binding studies show that butyrate treatment does not significantly affect the amount or the hormone-binding affinity of the glucocorticoid receptor. In a transient transfection assay, glucocorticoid hormone can activate transcription from a MMTV long terminal repeat-driven luciferase gene construct equivalently in untreated and butyrate-treated cells, indicating that the soluble factors necessary for transactivation of the MMTV promoter are unaffected by butyrate. The differential effect of butyrate on the induction of stable chromatin templates and transiently expressed plasmids suggests that butyrate prevents nucleosome displacement and represses transcription by inducing a modification of chromatin.

Animals↗

PubMed1990

Wnt-3, a gene activated by proviral insertion in mouse mammary tumors, is homologous to int-1/Wnt-1 and is normally expressed in mouse embryos and adult brain.

We have isolated a common insertion site, Wnt-3, for proviruses of the mouse mammary tumor virus (MMTV). Of mammary tumors induced by the GR variant of MMTV, 5% contains a provirus at Wnt-3, which is located on mouse chromosome 11. The gene is transcribed into a 3.8-kilobase (kb) mRNA in tumors with nearby proviral insertions but not in tumors with proviruses at other loci or in most adult tissues. Normal expression of Wnt-3 is detected in mouse embryos (with a peak around day 12 of gestation) and at low levels in adult brain. The transcriptional unit of the Wnt-3 gene spans approximately 55 kb, with a first intron of 36 kb. The deduced amino acid sequence of the Wnt-3 protein is 47% identical to the int-1/Wnt-1 gene product.

Amino Acid Sequence↗

PubMed1990

Prolactin effects on the dietary regulation of mouse mammary tumor virus proviral DNA expression.

Chronic energy-intake restriction inhibits mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice by greater than 90%. We have shown that associated with suppression of mammary tumorigenesis there is a reduction or inhibition of circulating prolactin, MMTV particles expressed, and MMTV mRNA transcription in mammary glands (and in most organs tested). To understand the concerted action of prolactin, energy-consumption level, and MMTV on inducing mammary tumors, experiments were designed to control prolactin and energy levels in order to evaluate their effects on MMTV mRNA expression. Mice on restricted diets were grafted with adenohypophyses, and mice fed ad libitum were treated with the dopaminomimetic agent octahydrobenzo [g]quinoline. Adenohypophyseal grafting significantly increased prolactin in dietary (energy)-restricted mice, and this effect was associated with an increase in MMTV mRNA expression within the mammary gland; a linear correlation between prolactin levels and MMTV mRNA expression in the mammary gland was found. Conversely, elimination of the nocturnal peak of circulating prolactin by i.p. injection of dopaminomimetic octahydrobenzo [g]quinoline to mice fed ad libitum delayed (by 8 weeks) and reduced (even as long as 25 weeks) mammary gland MMTV mRNA expression. These findings associate prolactin influences with MMTV mRNA production in mice and help explain the link between chronic energy-intake restriction and reduced MMTV gene expression.

Aminoquinolines↗

PubMed1990

Suppression of mouse mammary tumor proviral DNA and protooncogene expression: association with nutritional regulation of mammary tumor development.

Chronic energy intake restriction (CEIR) reduces mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice. Fewer than 10% of C3H/Ou mice developed mammary tumors during 88 wk of study when subjected to CEIR regardless of calorie source (fat vs. carbohydrate). By contrast, 100% of mice fed ad libitum diets relatively high in fat or carbohydrate or a commercial diet developed tumors by 35-40 wk. MMTV proviral DNA transcription was shown to be activated in spleen, liver, lung, kidney, small intestine, and mammary gland of mice consuming these diets ad libitum. By contrast, these messages were suppressed by CEIR in all tissues analyzed except spleen. MMTV proviral messages in liver and mammary gland increased with age in full-fed mice and were suppressed by CEIR. These findings suggest that the nutritional regulation of MMTV proviral DNA expression is tissue-specific. In CEIR mice the suppressed MMTV proviral DNA transcripts in mammary gland and liver increased with time in association with the delayed onset of mammary tumors. Mammary tumorigenesis in C3H mice is associated with integration of MMTV proviral DNA, which appears to activate a putative mammary tumor protooncogene, int-1. CEIR apparently decreases the frequency of viral reintegration adjacent to the int-1 gene and thus inhibits expression of int-1 and probably an initiation step in mammary tumorigenesis. Expression of other putative protooncogenes, int-2 and ras, in liver tissue was also reduced by CEIR. These findings indicate that both initiation and promotion of mammary tumorigenesis are influenced by CEIR in C3H/Ou mice.

Animals↗

PubMed1993

Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4.

Transgenic mice carrying the Wnt-1 protooncogene modified for expression in mammary epithelial cells exhibit hyperplastic mammary glands and stochastically develop mammary carcinomas, suggesting that additional events are necessary for tumorigenesis. To induce such events and to identify the genes involved, we have infected Wnt-1 transgenic mice with mouse mammary tumor virus (MMTV), intending to insertionally activate, and thereby molecularly tag, cooperating protooncogenes. Infection of breeding female Wnt-1 transgenics decreased the average age at which tumors appeared from approximately 4 months to approximately 2.5 months and increased the average number of primary tumors per mouse from 1-2 to > 5. A smaller effect was observed in virgin females, and infection of transgenic males showed no significant effect on tumor latency. More than half of the tumors from the infected breeding group contained one or more newly acquired MMTV proviruses in a pattern suggesting that most cells in tumors arose from a single infected cell. Analyses of provirus-containing tumors for induced or altered expression of int-2/Fgf-3, hst/Fgf-4, int-3, and Wnt-3 showed activation of int-2 in 39% of tumors, hst in 3%, and both int-2 and hst in 3%. DNA analyses with probes for protooncogenes and MMTV confirmed that the activations resulted from proviral insertions. There was no evidence for proviral insertions at the int-3, Wnt-3, or Wnt-1 loci. These findings provide further evidence that fibroblast growth factors Int-2 and Hst can cooperate with Wnt-1, another secreted factor, in mammary tumorigenesis, and they illustrate the capacity of this system to identify cooperating oncogenes.

Animals↗

PubMed1995

Mammary tumor suppression by transforming growth factor beta 1 transgene expression.

In cell culture, type alpha transforming growth factor (TGF-alpha) stimulates epithelial cell growth, whereas TGF-beta 1 overrides this stimulatory effect and is growth inhibitory. Transgenic mice that overexpress TGF-alpha under control of the mouse mammary tumor virus (MMTV) promoter/enhancer exhibit mammary ductal hyperplasia and stochastic development of mammary carcinomas, a process that can be accelerated by administration of the chemical carcinogen 7,12-dimethylbenz[a]anthracene. MMTV-TGF-beta 1 transgenic mice display mammary ductal hypoplasia and do not develop mammary tumors. We report that in crossbreeding experiments involving the production of mice carrying both the MMTV-TGF-beta 1 and MMTV-TGF-alpha transgenes, there is marked suppression of mammary tumor formation and that MMTV-TGF-beta 1 transgenic mice are resistant to 7,12-dimethylbenz[a]anthracene-induced mammary tumor formation. These data demonstrate that overexpression of TGF-beta 1 in vivo can markedly suppress mammary tumor development.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1995

Induction of mammary epithelial hyperplasias and mammary tumors in transgenic mice expressing a murine mammary tumor virus/activated c-src fusion gene.

Activation of the c-Src tyrosine kinase has been implicated as an important step in the induction of mammary tumors in both mice and humans. To directly assess the effect of mammary gland-specific expression of activated c-Src, we established transgenic mice that carry a constitutively activated form of c-src under transcriptional control of the murine mammary tumor virus long terminal repeat. Female mice derived from several independent transgenic lines lactate poorly as a consequence of an impairment in normal mammary epithelial development. In addition to this lactation defect, female mice frequently develop mammary epithelial hyperplasias, which occasionally progress to frank neoplasias. Taken together, these observations suggest that expression of activated c-Src in the mammary epithelium of transgenic mice is not sufficient for induction of mammary tumors.

Aging↗