Spontaneous Mammary Tumors In Mice Research Articles

Energy restriction and the risk of spontaneous mammary tumors in mice: a meta-analysis.

Our meta-analysis was aimed at providing a systematic review of the literature regarding the effect of energy restriction on spontaneous mammary tumors in mice and at providing a more precise pooled (summary) estimate of the risk of mammary tumors. A sensitivity analysis was conducted to obtain insight in potential heterogeneity between the animal studies. A literature search was conducted with the following terms to identify relevant articles: animal studies, mammary tumors, fat restricted, dietary carbohydrates, energy restriction and calorie restriction. A criteria list for the assessment of quality items (i.e., study characteristics) in animal experiments was developed that was intended to quantitatively assess potential factors that underlie heterogeneous results of different animal experiments. Incidence figures were used to calculate the risk difference. The pooled risk difference was calculated by random effects meta regression analysis. Fourteen animal experiments were included in this meta-analysis. Publication bias could not be identified. The pooled risk difference for the 14 studies was -0.55 with a narrow 95% confidence interval (-0.69; -0.41), implying that the energy-restricted animal groups developed 55% less mammary tumors than the control groups. No heterogeneity could be detected between the studies based on study characteristics that included the age of mice at the start of intervention, duration of intervention, allocation of the mice, use of ad libitum control group, fertility of the mice and the type of energy-providing nutrient (fat, carbohydrate or protein). This meta-analysis confirms that energy restriction in itself consistently protects against the development of mammary tumor in mice, irrespective of the type of restricted nutrient or other study characteristics.

Validity of mouse mammary tumour models for human breast cancer: Comparative pathology

In March 1999, a panel of distinguished pathologists was convened by the U.S. National Institutes of Health Breast Cancer Think Tank to develop a classification of breast lesions based on their examination of 39 models of Genetically Engineered Mice (GEM) associated mouse mammary cancer (Cardiff et al., 2000). The meeting, in Annapolis, Maryland, resulted in a published summary report from the Pathology Panel (Cardiff et al., 2000). The Annapolis consensus report, developed from the Panel's deliberations, pointed out that the mammary lesions of GEM were different from most (spontaneous) mouse mammary tumors and could be divided into three distinct categories: (1) lesions that resemble those found in spontaneous mouse mammary tumorigenesis, (2) lesions that have a unique “signature” tumor phenotype that was specific for the transgene, and (3) lesions that resemble those found in human breast diseases (Cardiff et al., 2000). This review emphasizes the proposed nomenclature and the differences between the models and human breast cancer with the intention of stimulating discussion and the development of new models. Microsc. Res. Tech. 52:224–230, 2001. © 2001 Wiley-Liss, Inc.

A novel non-mouse mammary tumor virus activation of the Int-3 gene in a spontaneous mouse mammary tumor.

In a mouse mammary tumor model system in which carcinogenic progression can be investigated, we have found a unique mutation of Int-3 associated with progression from premalignant lobular hyperplasia to tumor. Sequence analysis of the rearranged fragment revealed an insertion of an intracisternal type A particle (IAP) within the Int-3 gene. Int-3 is mutated frequently in mouse mammary tumor virus (MMTV)-induced mammary tumors by insertion of MMTV proviral DNA into this intragenic region. In these mutations, the insertion produces a chimeric Int-3 transcript encoding the cytoplasmic portion of the Int-3 protein driven by the MMTV long terminal repeat promoter. In this case, the IAP DNA was inserted in the opposite transcriptional orientation relative to Int-3; nevertheless, a similar chimeric RNA transcript driven by a cryptic promoter in the oppositely oriented 5' IAP long terminal repeat was generated. This is the first demonstration that an insertional mutation unrelated to MMTV activates an Int gene commonly associated with mammary tumorigenesis.

Inhibition by Guan-mu-tong (Caulls aristolochiae manshuriensis) of the growth of spontaneous mammary tumors in SHN virgin mice

Multiparous SHN mice with spontaneous mammary tumors (5-10 mm in size) were given water extract of Guan-mu-tong (Gmt; Caulis aristolochiae manshuriensis) (0.5%) ad libitum as drinking water for 10 days. This treatment retarded significantly the growth of mammary tumors compared with the controls. By contrast, normal mammary gland growth, histology of adrenals and ovaries, and body weight were affected little by the Gmt treatment. Gmt appears to be the first agent inhibiting the growth of spontaneous mouse mammary tumors of palpable size by per os treatment.

Iron enhances tumor growth. Observation on spontaneous mammary tumors in mice.

Iron is essential for the growth of all cells, including tumor cells. The authors previously reported that a variety of transplantable tumors grew faster and larger in mice that were on an iron-rich diet compared with those on an iron-deficient diet. In this study the authors examined the relationship between iron in the diet and development of tumors in mice that are known to develop spontaneous tumors--C3H/HeN-MTV+(C3H-MTV+) mice that were congenitally infected with mammary tumor virus. These mice have a greater than 96% chance of developing mammary tumors between the ages of 7.2 and 9.2 months. Fifteen C3H-MTV+ weanlings were given a low-iron diet (5 mg iron/kg diet), and 15 were given diets with normal amounts of iron (180 mg Fe/kg diet). Thirteen of the 15 mice from the low-iron group and all 15 mice from the normal-iron group developed tumors. The average tumor growth rate in the normal-iron group was 112%/wk, compared with 62%/wk for the low-iron group. The difference in tumor growth rate between the two groups was significant (P = 0.02 by Student's t test). In this study, low iron intake did not prevent tumor development, but the results confirm the authors' previous report that iron nutrition of the host affects tumor growth; tumors grow better in an iron-rich environment. High levels of iron in the diet may enhance tumor growth, and this should be considered when treating patients with cancer.

Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice

Indole-3-carbinol (I3C) is a potent inducer of cytochrome P450 enzymes in many species, including humans. We therefore studied alterations in the cytochrome P450-dependent metabolism of estradiol in different strains of mice consuming I3C in semisynthetic powdered diets at doses ranging from 250 to 5000 p.p.m. (34-700 mg/kg/day) for different periods of time. In short-term metabolic studies (3 weeks), wet liver weight increased in SW and C3H/OuJ mice in a dose-responsive manner. Dietary I3C increased the cytochrome P450 content measured in hepatic microsomes, as well as the extent of estradiol 2-hydroxylation, up to 5-fold. In a long-term feeding experiment (8 months), female C3H/OuJ mice consumed synthetic diets containing I3C at 0, 500 or 2000 p.p.m. Mammary tumor incidence and multiplicity were significantly lower at both doses of I3C, and tumor latency was prolonged in the high-dose group. We conclude that I3C is an inducer of hepatic P450-dependent estrogen metabolism in mice, and that it is chemopreventive in the C3H/OuJ mouse mammary tumor model. This protective effect may be mediated in part by the increased 2-hydroxylation and consequent inactivation of endogenous estrogens.

DNA rearrangements of the int region in spontaneous mouse mammary tumors of SHN/S and SLN/S mice

SHN and SLN mice originating from the same Swiss albino stock are genetically very close to each other. The incidence and latent period of mammary tumor development in SHN mice were higher and shorter than those in SLN. To elucidate these differences in the behavior of mammary tumorigenesis, the frequency of insertion of mammary tumor viral genes within the int-1 and int-2 regions in spontaneous mammary tumors from their two substrains, SHN/S and SLN/S, were compared. The frequency of provirus integration into either int-1 or int-2 in DNAs from mammary tumors was 52% ( 11 21 ) in SHN/S and 45% ( 5 11 ) in SLN/S. The frequency of insertion within int-1 or int-2 could not account for the different susceptibilities of SHN/S and SLN/S.

Immunocytochemical detection of estrogen receptors in a hormone-unresponsive mammary tumor.

A combination of two monoclonal antibodies and high resolution immunocytochemical technique was applied to label estrogen receptors in spontaneous mouse mammary tumors. Protein A-colloidal gold complex was used as an electron opaque marker. With this procedure estrogen receptors were labelled in the nuclei of cancer cells, predominantly over heterochromatin. In the cytoplasm a slight tagging of the rough endoplasmic reticulum was detected, apparently related with the sites of receptor biosynthesis. Other organelles and the mammary tumor viruses (MuMTV) were not stained immunocytochemically. The immunocytochemical procedure applied in this investigation allowed the detection of low levels of estrogen receptors in an estrogen-unresponsive mammary carcinoma. The presence of estrogen receptors with a specific distribution in estrogen-independent tumors suggests the need of a reevaluation of their capacity as indicators of hormone-dependence in mammary carcinomas.

Variation of glycosaminoglycan in the growth of transplantable tumors derived from a spontaneous ddY mouse mammary tumor

The components and variations of glycosaminoglycan (GAG) in the growth of transplantable tumors derived from a spontaneous mouse mammary tumor were investigated. A 45-week-old ddY female mouse, obtained from Shizuoka Laboratory Animal Center, was found to have a bean-sized mass at the third mammary gland of the left side. The tumor mass was surgically excised and used for transplantation in the present study. This mammary tumor was histologically found to be Type B-adenocarcinoma. Transplantable mammary tumors consisted of the fibrous or edematous interstitium contained a large amount of GAG components, which was mainly hyaluronic acid (HA), dermatan sulfate (DS) and chondroitin sulfate A/C (ChS). In the analysis of GAG components, HA content was present in a large amount in logarithmic growth phase of transplanted mammary tumors, but it was markedly decreased in stationary phase. On the other hand, the contents of DS and ChS increased in stationary phase of the tumor growth, and these increases corresponded, histologically, with the propagation of the fibrous interstitial tissues.

Inhibition by indomethacin of spontaneous mammary tumorigenesis in SHN mice.

This experiment was designed to examine the effects of indomethacin, a potent prostaglandin synthesis inhibitor, on spontaneous mammary tumors in mice. The growth of established mammary tumors and the appearance of new tumors in multiparous SHN mice were significantly suppressed by the subcutaneous implantation of pellets of indomethacin diluted to 1/12 with cholesterol. Furthermore, the same treatment inhibited normal and preneoplastic mammary gland growth in virgin SHN mice. The pattern of estrous cycles, ovarian structure, and plasma prolactin levels were not affected significantly by the treatment. All results have demonstrated that indomethacin inhibits mammary tumorigenesis of mice primarily by route(s) other than the endocrine system under the present experimental conditions. Indomethacin would be the first agent that appears to inhibit the growth of spontaneous mammary tumors of palpable size in mice.

Prolactin as a promoter of initial progression of spontaneous mammary tumors in mice and lack of relationship to age

In a high mammary tumor strain of SHN virgin mice, the percent increase in the number of palpable mammary tumors during 3 weeks after the 1st tumor appearance was significantly retarded by ovariectomy and this retardation was prevented by pituitary grafting associated with the decrease and the increase in the circulating prolactin levels, respectively. A low mammary tumor strain of SLN virgin mice grafted with a single pituitary each at 2 and 5 months of ages developed mammary tumors 4 and 2 months after grafting (6 and 7 months of ages), respectively. However, there was no difference between groups in mammary tumor incidence at any month after mice in each group developed tumors first. Mammary tumor incidences of both groups were significantly higher than that of the untreated control at all ages examined. These findings have demonstrated that prolactin plays a key role in the initial progression of spontaneous mammary tumors of mice besides its prerequisite role in tumor development. They also suggest that there is no intrinsically age-related difference in prolactin effect on mammary tumorigenesis.

Modification of spontaneous mammary tumors in mice fed different sources of protein, fat and carbohydrate

The effects of different sources of dietary protein (milk, soy, wheat, fish and beef), fat (corn oil and butter), and carbohydrate (dextrin and sucrose) on the development of spontaneous mammary tumors in virgin female C3H/HeJ mice were investigated. Weanling mice were randomly divided (28 mice/group) and fed ad libitum one of 14 equicaloric diets containing either 11% or 33% protein and 5% or 30% fat or a standard mouse feed for approximately 2 years. Beginning at 6 months of age, tumor incidence, non-specific deaths, individual weights and amount of food consumed were monitored Variations in tumor incidence were most pronounced when the mice fed different sources of protein (at a high level) were compared. The mice fed the low fat diets containing either low milk protein (high carbohydrate) or high fish protein generally exhibited the lowest tumor incidence and highest percent survival. High weight gain was correlated with early tumor appearance, but not with tumor incidence later in the experiment. The mice fed a low fat diet containing low milk protein were tumor-free significantly longer than mice fed the diets containing fish or beef. The only groups with 100% tumor incidence by 120 weeks of age were those fed diets containing sucrose (table sugar) or a high fat level.

The early detection of host immune response to spontaneous mouse mammary tumors by leukocyte adherence inhibition

Longitudinal testing of C3H/HeJ female mice was carried out over a 52-week period with the leukocyte adherence inhibition (LAI) assay using solubilized tumor antigen prepared by 3 M KCl extraction. During this period, 75% of the mice developed histologically confirmed mammary adenocarcinomas. Of those mice 93% had a statistically significant P < 0.01) LAI response to soluble mammary tumor antigen prior to first detection of tumors by palpation. Five percent of the test group developed statistically significant LAI responses without development of detectable mammary tumors within a 34-week observation period. The first significant LAI reactivity of individual mice preceded the first detection of tumors by an average of more than 17 weeks.

Precursor Lesions and Pathogenesis of Spontaneous Mammary Tumors in Mice

A histologic study was done on the spontaneously occuring precursor and neoplastic lesions of mammary gland in inbred and hybrid female mice. Hyperplastic alveolar nodules (HAN) are small groups of non-encapsulated mammary acini lined by a single layer of low cubodial epithelial cells. The stroma of HAN often contain macrophages laden with ceroid pigment, which imparts to them a yellow color. Microfoci of carcinoma may be found within HAN, and adenoacanthomas may arise within acini in which there is chronic inflammation. Plaques are pregnancy-dependent lesions which occur in three albino mouse strains: DD, GRS, and RIII. These plaques are disc-shaped, are circumscribed or unencapsulated, have a central myxomatous core, and have acini which exhibit radial symmetry. Plaques can give rise to adenocarcinomas type P, type B (papillary and cystic) and also to the unusual and distinctive pale cell carcinoma. The spontaneous tumors described in this paper are mammary gland adenocarcinomas with sebaceous cell nests, tumors which are papillomas and contain basal epithelial elements and acini derived from mammary, sebaceous glands, or hair follicles.

Effects of dietary selenium and of lead on the genesis of spontaneous mammary tumors in mice

Selenium added to the diet significantly lowers the incidence of spontaneous mammary adenocarcinoma in female inbred C3H/St mice infected with the Bittner Milk Factor. Lead, 5 ppm, added to the drinking water in the form of the acetate, diminishes the uptake of selenium and reduces its anticarcinogenic effects, causing mammary tumors to appear with the same high incidence as in Se-unsupplemented controls. At higher lead concentrations in the drinking water (25 ppm), the overall tumor incidence is lowered, but tumor growth is significantly accelerated and the survival of tumor-bearing mice is shortened. Under the conditions of administration chosen, lead acts as a selenium antagonist and lowers the concentrations of selenium in liver, kidney, and spleen. The deposition of selenium, copper, and arsenic in bone is increased as compared to lead-unexposed controls.

Characterization of lymphocyte subsets in spontaneous mouse mammary tumors and host lymphoid organs.

The subsets of small lymphocytes (surface Igm-positive or B, Thy-I-positive or T and "double-negative" or null) appearing within spontaneous mammary tumors of C3H retired breeder female mice and in various lymphoid organs of the host at different stages of tumor development were characterized directly using a radioautographic method. Tumor-bearing mice showed early transient splenomegaly and progressive atrophy of the thymus. The proportion of T small lymphocytes increased with tumor age within the tumor and in the spleen, blood and thymus; then, except in the spleen, these proportions declined again by 8 weeks of tumor growth. The incidence of B small lymphocytes showed no change in the tumor or thymus; there was an increase in the blood after 3 weeks, and a small decrease in the spleen after 7 weeks. At all the sites examined, the proportion of null small lymphocytes declined from an initial high level observed in the elderly tumor-free control mice, and then recovered to control levels after 7 weeks. The absolute numbers of T and null cells in the spleen changed in parallel to their proportions, while splenic B-cell numbers increased at 1-3 weeks. In the thymus the absolute numbers of all subsets decreased, with a late recovery of null cell numbers. Age-matched control mice showed higher proportions of null cells in the spleen, blood and thymus, and lower proportions of T cells in the blood and spleen, than did young normal mice. This spontaneous tumor appears to be characterized by an increase in T cells, rather than in null cells, as observed for rapidly growing transplanted tumors. The null cell rise in the present case takes place before the clinical appearance of tumors. In both cases, however, tumor-infiltrating B cells exhibited low levels of surface Ig, possibly related to a low level of maturation. The functional significance of these findings remains to be determined.

Mammary neoplasia in animals: pathologic aspects and the effects of contraceptive steroids.

The incidence of spontaneous tumors of the mammary gland varies greatly among the different mammalian species. Large domesticated animals have a very low frequency of the disease. Even though the cow has enormous mammary gland development and cows numbering in the millions are observed to an old age, less than 50 cases have been reported in the literature. Similarly, mammary tumors are equally rare in sheep, horses, pigs, and goats. In contrast, the incidence of mammary tumors in the dog exceeds that of women by a factor of 3 to 4, and the disease is common in the cat. Rats and mice have a high incidence of mammary tumors; however, they are less frequent in other species of small laboratory animals. Mammary neoplasms are apparently rare in the nonhuman primate, but interest in the disease in these animals remains high as they have a menstrual cycle comparable to women. This paper reviews some major aspects of spontaneous mammary tumors in mice, rats, cats, dogs, and nonhuman primates. Emphasis has been placed on the pathologic aspects of the neoplasms and the use of these species in the carcinogenic testing of contraceptive steroids. The literature contains a large number of excellent publications on mammary neoplasia in animals; only selected articles are cited. The reader is especially referred to the comprehensive review by Hamilton published in 1974 [32] and the review by STEWART published in 1976 [68] on the comparative pathology of animal neoplasia.KeywordsMammary GlandMouse Mammary Tumor VirusTubular AdenocarcinomaMammary NoduleContraceptive SteroidThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Combined low dose-rate hyperthermal treatment: A model for interstitial therapy

This-d generation transplants of spontaneous mouse mammary tumors were subjected to a continuous hyperthermal and low dose-rate treatment at dose rates comparable to interstitial radium needle therapy. Radiation was delivered via co-60 and heating was by immersion in a water bath. Treatment temperatures were fl:om 37.5 to 42.OoC with treatment times up to 36 hours. As judged by tumor regrowth times, the combined treatment was about 6 times more effective at 42.0 than at 37.5oC. There was little increase in sensitivity from 37.5-410, but the sensitivity doubled for each 0.42OC increase in temperature above 41.OoC.

Combined effect of cyclocytidine and lentinan of spontaneous mammary tumors in mice.

Cytotoxic cytidine analog, cyclocytidine, and antitumor immunopotentiator, lentinan, offered an opportunity of testing the effect of combined modality of cytocidal agent and immunopotentiator on spontaneous mammary tumors of mice. Lentinan did not improve the therapeutic effect of cyclocytidine; it only prevented the early toxic death of mice due to cyclocytidine in one strain of mice but not in the other strain.

Immediate effects of insulin and anti-insulins on glycolysis in spontaneous mammary tumors in mice.

Glucolysis in spontaneous mouse mammary tumors in vitro with 0.2% glucose was inhibited 20–40% by 200 μg/cc Δ1-testololactone or 20 μg/cc testosterone (“anti-insulins”). Addition of insulin gave small but significant stimulations (8–15%) of glucolysis. Similar effects of insulin and Δ1-testololactone were obtained with fructose, but high levels of the sugar were required (2.7–5.4%.) This seems based on the greatly lowered affinity of the hexokinase for fructose. The reported effects of insulin in stimulating various anabolic functions (DNA polymerase, DNA synthesis, cell growth) require hours (4, more or less) for expression, whereas enhancement of glucolysis takes place in 5–10 minutes. The primary target for insulin in all these cases may be glucolysi.