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PubMed1979

Bioactivities and the effect of dilution on various milk-borne murine mammary tumor viruses.

Infectivity titrations of milk-borne murine mammary tumor virus (MuMTV) from different sources or prepared in different ways or stored for periods of time have been compared. Titration curves were in general reproducible for MuMTVs of different sources or handled in different ways and for different methods of measurement, such as hyperplastic alveolar nodule (HAN) development, tumor development, or MuMTV antigen secretion in third-lactation milk, The curves had characteristic shapes with a low incidence of infection at low dilutions of milk, high incidences at intermediate dilutions, and low incidences at high dilutions. Infectivity incidences were unaffected by dilution over the range 10(-2) to 10(-5). The curves did not change appreciably with time of storage of milk at liquid N2 temperature for periods up to 3 years. Rate zonal fractionation of RIII milk gave zones with bioactivities which were not proportional to B-particle content. Upon dilution, the bioactivity of Zone 3, rich in B particles, and Zone 5, poor in B particles, increased, while the bioactivity of all the other zones usually decreased with dilution. The low incidence of infection at low dilutions may have been due, in part, to an immune response of the inoculated mouse. Administration of inactivated virions 4 h prior to or with MuMTV inoculations gave some evidence in support of this hypothesis but the complexity of the bioassay system for MuMTV lends uncertainty to interpretation of results.

Age Factors↗
PubMed1980

Age- and tumor-correlated changes in functional antibody responses to MTV in neonatally infected mice.

BALB/cfC3H female mice (neonatally infected with MTV) possess several different specific antibody activities measured functionally by reactivity with MTV-associated antigens expressed on the surface of isologous MTV-induced mammary tumor target cells. All females when young develop serum antibody which can block specific T-cell cytotoxic activity of BALB/cfC3H spleen cells; this activity remains detectable throughout life. In addition, recruiting antibody is found in the post-weaning stage. This recruiting activity is apparently directed against the same antigenicity as the blocking activity; it can be detected only rarely in whole serum but is revealed in the 19S fraction when the competing blocking antibodies are sequestered into the 7S fraction. In mid-adult life, 19S recruiting activity is found in only a few of the females; the incidence increases as the females age, and it occurs earlier in those females which subsequently develop mammary tumors. A third antibody activity of serum is blocking factor directed against different MTV-associated tumor-cell-surface antigenicity; this blocks the antibody-dependent cell-mediated cytotoxicity characteristic of spleen cells from BALB/c females horizontally exposed to MTV-associated antigenicity. This blocking activity of serum is not found in young females, and in the older females it is more frequent in those which develop mammary tumors.

Age Factors↗
PubMed1980

Quantification of mouse mammary tumor virus structural proteins in hormone-induced mammary tumors of low mammary tumor mouse strains.

The expression of the mouse mammary tumor virus (MMTV) in hormone-induced mammary tumors was investigated by means of a radioimmunoassay for two major MMTV proteins, gp52 and p27. MMTV proteins were isolated on lectin affinity- and ion-exchange chromatography columns. The purified viral proteins were electrophoretically homogeneous and retained immunoreactivity after labelling with 125iodine. Standard competition assays showed that group-specific antigenic determinants were reacting. Mammary tumors were induced in three strains of mice with a low natural incidence of mammary tumors, C57BL, O20 and C3Hf, by a combined hormone treatment, consisting of hypophyseal isografts and administration of progesterone and estrone. Mammary tumors and mammary glands of hormone-treated animals were extracted and used for competition radioimmunoassays. In general, the tumorigenic hormone treatment resulted in enhanced amounts of MMTV proteins in the mammary glands, compared to the amounts found in lactating mammary glands of untreated animals. The levels of MMTV proteins in the mammary tumors were lower than in the mammary glands.

Animals↗
PubMed1980

The effect of diet on autogenous immunity to mouse mammary tumor virus in C3H/Bi mice.

Antibody levels to mouse mammary tumor virus (MuMTV) in sera of C3H/Bi, C57BL/6 and AKR mice were assayed by an enzyme-linked immunosorbent assay (ELISA). It was found that antibody levels to MuMTV were highest in sera of C3H/Bi females which have a high incidence of breast cancer and low in male C3H/Bi and female C3H/Bi foster-nursed on C57BL/6 females. Sera of C57BL/6 and AKR mice showed very low or undetectable levels of antibody to MuMTV. Reduction of caloric intake sufficient to inhibit mammary tumor formation strikingly inhibited formation of antibody against MuMTV. The lowest levels of antibody were observed in sera of mice fed 10 cal/day of a defined diet. Significantly higher levels developed in the sera of mice fed 16 cal/day of the same defined diet. The highest antibody levels against MuMTV, however, were seen in sera of mice fed lab chow ad libitum but no correlation was evident between levels of antibody and tumor size. These studies indicate that dietary caloric restriction has a profound influence on the development of both mammary adenocarcinoma and antibody responses to MuMTV.

Age Factors↗
PubMed1987

MHC-controlled susceptibility to C3H-MTV-induced mouse mammary tumors is predominantly systemic rather than local.

The major histocompatibility complex (MHC) is one of the genetic factors involved in the control of susceptibility to MTV-induced mammary tumors in mice. Previously, genetic differences in mammary tumor susceptibility were shown to be mainly due to differences in susceptibility of the mammary gland itself. Such experiments, however, were carried out using inbred strains which differ in many genes. Therefore, the conclusion drawn from such experiments is not necessarily applicable to every gene involved. We tested whether in the strain C57BL/10 (B10, resistant) and the H-2 congeneic strain B10.A(5R) (5R, susceptible), which differ only at the MHC, the MHC-controlled difference in tumor susceptibility indeed resides in the mammary gland tissue itself, or is caused by systemic factors. Mammary glands of infant B10 and 5R mice were transplanted into mammary fat pads of C3H-MTV-infected mammectomized (B10 X 5R)F1 females. The hosts received a hypophyseal isograft under the kidney capsule or were subjected to force-breeding to provide hormonal stimulation necessary for mammary tumor development. Control groups of C3H-MTV-infected B10, 5R and (B10 X 5R)F1 females and (B10 X 5R)F1 females without C3H-MTV were also subjected to the 2 types of hormonal stimulation. There was no difference in susceptibility between the 5R and B10 mammary glands transplanted into C3H-MTV-infected F1 hybrid hosts. On the other hand, C3H-MTV-infected 5R and (B10 X 5R)F1 females were significantly more susceptible than the C3H-MTV-infected B10 females, when either of the 2 methods of hormonal stimulation was used. This indicates that, in the strains used, MHC-controlled susceptibility to C3H-MTV-induced mammary tumorigenesis is predominantly or exclusively controlled by systemic factors rather than by factors residing in the target tissue.

Animals↗
PubMed1987

Activation of endogenous MMTV proviruses in murine mammary cancer induced by chemical carcinogen.

A study was undertaken to determine whether activation of expression of silent endogenous mouse mammary tumor virus (MMTV) proviruses may occur during tumor induction by a chemical carcinogen. A series of transplantable mammary tumors induced in BALB/c mice by treatment with dimethylbenz(alpha)anthracene (DMBA), pituitary isograft, or both was examined. The results obtained suggest that chemical carcinogens may induce mammary tumors through more than one pathway. Two of 9 tumor lines produced virus-specific products at levels above those observed during the course of normal mammary gland development. One tumor contained high levels of MMTV-specific envelope [3.8 kilobase (kb)] and genomic length (8.9 kb) RNAs. This tumor expressed core- and envelope-related proteins detectable by immunoblotting (including p28, gp52, and gp36), displayed an acquired provirus with a restriction map different from those of described exogenous MMTV strains, and contained abundant virus particles. The other tumor that expressed high levels of MMTV gene products contained envelope-specific (3.8 kb) and long-terminal-repeat-specific (1.6 kb) messages but no full-length RNA. It exhibited an aberrant 39 kDa, envelope-related protein, but no virus particles. Methylation data implicated the usually silent endogenous Mtv-8 provirus as the source of the abnormal envelope protein. None of the tumors expressed RNA from the putative mammary oncogenes, int-1 or int-2. We propose that chemical carcinogens may activate different cellular genes by mutation and that, in a subset of DMBA-induced mammary tumors, the target genes include endogenous MMTV proviruses that are normally not expressed. The effect on provirus expression varies from tumor to tumor, but is stable over passage of a given tumor. MMTV may be of etiological importance in the genesis of those DMBA-induced tumors which contain high levels of MMTV-specific products, but its action in the BALB/c system is not mediated through enhanced expression of the int-1 or int-2 preferred integration regions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas.

The BALB/cf/Cd substrain of mice, developed by inbreeding and selection, shows a 70% incidence of spontaneous kidney adenocarcinomas. Initially foster-nursed on C3H mothers, these mice no longer produce mammary tumors, but there is evidence that mouse mammary tumor virus (MMTV) is involved in the formation of these renal carcinomas. We identified a chromosomal region called int-41, representing a locus interrupted by the integration of an exogenous MMTV provirus in a BALB/c mammary tumor. We found a DNA rearrangement and transcriptional activation in the domain specified by the int-41 probe in one primary kidney adenocarcinoma. A 5.2-kb int-41 specific mRNA was detected in the kidney tumor cell line established from a transplantable renal adenocarcinoma. This mRNA hybridized with MMTV and int-41 specific probes suggesting that it is a hybrid molecule composed of MMTV-LTR sequences covalently linked to host cell RNA. This mRNA was strongly stimulated by the presence of glucocorticoid hormone in the culture medium. Our data are compatible with the hypothesis that the int-41 chromosomal domain is involved in the neoplastic transformation of epithelial cells from different organs.

Adenocarcinoma↗
PubMed1987

Oncogene expression during progression of mouse mammary tumor cells; activity of a proviral enhancer and the resulting expression of int-2 is influenced by the state of differentiation.

The RAC cell lines are derived from a mammary tumor induced by the mouse mammary tumor virus (MMTV). Polygonal cells have retained many characteristics of epithelial cells and induce adenocarcinomas; cuboidal cells are poorly tumorigenic; and elongated cells produce highly malignant sarcoma-like tumors. MMTV proviral integrations, one of which has cis-activated the int-2 gene, demonstrated that the lines are clonal descendents from a single tumor cell. Polygonal cells have a high constitutive expression of MMTV and contain int-2 RNA. In contrast, the cuboidal and the elongated cells show no detectable expression of int-2, even in the presence of glucocorticoid hormone. Transcription of MMTV in these cells is also low but can be stimulated by dexamethasone, albeit to levels lower than in polygonal cells. Thus, expression of int-2 seems to be caused by an enhancing activity on the MMTV provirus which is not dependent on steroid hormone and is specific for mammary tumor cells with epithelial characteristics. Progression in this cell system does not require sustained expression of int-2.

Adenocarcinoma↗
PubMed1987

Transfection of the int-1 mammary oncogene in cuboidal RAC mammary cell line results in morphological transformation and tumorigenicity.

The int-1 gene is often activated by proviral insertion in mouse mammary tumors. Direct evidence for the normal function of this gene and its role in tumorigenesis has therefore been lacking. To examine possible biological effects of int-1 activation in in vitro cell systems, we have constructed recombinant molecules of genomic int-1 DNA, transcriptionally activated by retroviral promoters. Transfection of these constructs into cuboidal RAC311C mammary cells leads to morphological transformation of the cells and rapid tumorigenicity.

Animals↗
PubMed1990

Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 1. Hydrochlorothiazide.

Toxicology and carcinogenesis studies of hydrochlorothiazide, a benzothiadiazide diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 15-day, 13-week and 2-year studies. No rats died during the 15-day or 13-week studies at dietary concentrations of up to 50,000 ppm. Deaths of male mice in the top dose group in the 13-week study were likely to be related to chemical administration. In the prechronic studies, increased nephrosis and mineralization at the kidney corticomedullary junction were the primary toxic effects of hydrochlorothiazide observed in rats. In mice, chemical-related effects included nephrosis and calculi, inflammation and epithelial hyperplasia in the urinary bladder. In 2-year studies using dietary concentrations of 0, 250, 500 and 2000 ppm in rats and 0, 2500 and 5000 ppm in mice, survival of dosed and control groups of rats and mice was similar, as were body weights of mice. Dosed groups of male and female rats were uniformly lighter than controls (up to 25%) throughout the studies. Severe chronic renal disease with secondary parathyroid hyperplasia and fibrous osteodystrophy of the bone were attributed to chemical administration in rats. No neoplasms in rats or female mice or non-neoplastic lesions in mice were associated with hydrochlorothiazide. In high-dose male mice, liver neoplasms were increased but were not considered to be related to hydrochlorothiazide administration because of an unusually low incidence in the control group relative to historical controls.

Adenofibroma↗
PubMed1987

Identification of androgen response elements in mouse mammary tumour virus and the rat prostate C3 gene.

The effect of steroid hormones on mouse mammary tumour virus (MMTV) promoter activity has been analysed in the breast cancer cell lines ZR-75-1 and T-47D 11. Both androgens and progestins were stimulatory in both cell lines, whereas glucocorticoids were stimulatory in only ZR-75 cells. A glucocorticoid response was restored to T-47D cells by the transient expression of a glucocorticoid receptor expression vector, suggesting that endogenous receptors were limiting. The effect of androgen was mediated by a region of MMTV previously shown to be essential for glucocorticoid and progestin responses between nucleotides -201 and -69 upstream of the cap site. Similarly, the effect of androgens on the rat prostate C3(1) gene promoter was analysed in the rat prostate cell line T5. Although these cells had functional androgen receptors which could stimulate MMTV-promoter activity, they were incapable of interacting with androgen response elements to stimulate transcription from the C3(1) promoter.

Androgens↗
PubMed1986

Glucocorticoid agonists as well as antagonists are effective inducers of mouse mammary tumor virus RNA in mouse mammary tumor cells treated with inhibitors of ADP-ribosylation.

Glucocorticoids increase expression of specific genes by a mechanism involving binding to and "activation" of a specific receptor protein. Other steroids, such as RU 486, bind to the glucocorticoid receptor but the resultant steroid-receptor complex is unable to activate glucocorticoid sensitive genes. In the present study we have observed that steroid regulation of the glucocorticoid-regulated mouse mammary tumor virus (MMTV) genome in cultured mouse mammary tumor cells is altered by treatment of the cells with inhibitors of (ADP-ribose)n synthetase. The ability of glucocorticoid agonists to increase MMTV is about 2-fold increased by the inhibitor treatment. Interestingly, RU 486 and other steroids that are normally inactive in control cells are very good inducers of MMTV in the treated cells. This alteration in MMTV expression is associated with a 37% increase in nuclear binding of the glucocorticoid, triamcinolone acetonide, and also RU 486 in the inhibitor-treated cells. Steroids that do not bind to the glucocorticoid receptor are not inducers in control or in treated cells. The results point to a role for ADP-ribosylation of proteins as a negative regulator of MMTV expression and suggest a mechanism for activation of steroid-sensitive genomes.

Adenosine Diphosphate↗
PubMed2005

Of mice, cats, and men: is human breast cancer a zoonosis?

Mouse mammary tumor virus (MMTV), a member of the betaretroviridae, is the most common cause of breast cancer (BC) in mice. MMTV is transmitted in mice both in the germline as endogenous proviruses and exogenously as infectious virions. Here, we review a variety of evidence accumulated for six decades that has suggested that a human homologue of MMTV may exist. The findings include recent studies from several independent laboratories that have detected sequences very closely related to MMTV in DNA isolated from human BC tumors. Other laboratories, however, have failed to detect the MMTV-related sequences in human DNA samples, and conclusive evidence for a human mammary tumor virus has been elusive. We also reviewed additional studies, suggesting that betaretroviruses are present in a much wider range of species than previously known, including rodents, felines, and primates. The observation that a subset of cats may be infected with a close homologue of MMTV may be of epidemiological significance for human BC. Cats may become infected by MMTV from mice, and in turn may transmit the virus to humans, possibly after selection for variants with an expanded host range.

Animals↗