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PubMed1985

Events in glucocorticoid hormone action. A correlation of histone H1 variant pattern changes, hormone binding to cell nuclei, and induction of mouse mammary tumor virus RNA.

To approach experimentally changes of chromatin structure introduced by glucocorticoids, the histone H1 compositions of hormone-treated and non-treated mouse mammary tumor cells of the GR line [Ringold, G., Lasfargues, E. Y., Bishop, J. M. and Varmus, H. E. (1975) Virology 65, 135-147] were compared. To define the biologically important hormone concentration range, the cells were exposed to different concentrations of triamcinolone, a synthetic glucocorticoid. The induction of mouse mammary tumor virus (MMTV) RNA was measured by cDNA excess hybridization, and the amount of hormone bound to nuclei was determined by a filter-binding assay. Between 0.3 nM and 30 nM triamcinolone the relative increase in nuclear bound hormone corresponded well with the relative induction of MMTV RNA. The half-life of triamcinolone in nuclei of growing cells was 1 h, as measured by a pulse-chase experiment. Reversed-phase high-performance liquid chromatography of histone H1 resulted in its separation into four subfractions. The treatment of cells with biologically active glucocorticoid, 3 nM or 30 nM triamcinolone or 1 microM dexamethasone, resulted in changes in the relative amounts of two subfractions and to a positional shift of two subfractions as compared to untreated cells. No changes were observed after exposure to 3 nM dexamethasone, a concentration which does not induce MMTV RNA [Ringold, G. M., Yamamoto, K. R., Tomkins, G. M., Bishop, J. M. and Varmus, H. E. (1975) Cell 6, 299-305].

Animals↗
PubMed2003

Novel murine mammary epithelial cell lines that form osteolytic bone metastases: effect of strain background on tumor homing.

We have developed a series of novel mammary epithelial cell lines from tumors arising in strain 129 mice, with the ultimate goal of evaluating the role of host factors in the development of bone metastases. Mammary tumors were induced in mice with subcutaneously implanted medroxyprogesterone acetate (MPA) pellets followed by administration of DMBA by oral gavage. Mammary tumor development was efficient in the 129 strain and was independent of osteopontin (OPN) expression. Epithelial cell lines were isolated from these tumors; surprisingly, these cells did not form tumors upon inoculation into the mammary fat pad of syngeneic mice, even when MPA was present. One OPN-deficient cell line was selected for further study; full transformation of these cells required expression of both polyoma middle T and activated ras. These doubly transfected cells, 1029 GP+Er3, grew in soft agar, and formed hormone-independent tumors efficiently in the mammary fat pad that spontaneously metastasized to several soft tissue sites but not to the bone. Derivatives of these cells were isolated from tumors arising in the fat pad and from a lung metastasis (r3T and r3L, respectively): these cells formed tumors more rapidly in the fat pad than the parental GP+Er3 cells. Upon left ventricle injection, the r3T and r3L cells formed osteolytic bone metastases in 129 mice, with few metastases seen in other organs. These tumors filled the marrow cavity, and caused extensive destruction of both cortical and trabecular bone. Intriguingly, in an alternative syngeneic host, (129xC57B1/6) F1, osteolytic bone metastases were not seen on x-ray; instead extensive liver metastasis was present in these mice, indicating that genetic factors in these two strains regulate tumor cell homing and distribution during metastasis. These cell lines provide an important new tool in the study of bone metastasis, particularly in elucidating the role of host factors in the development of these lesions, as the 129 mouse strain is frequently used for genetic manipulations in the mouse.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

Differential effects of p21(WAF1/CIP1) deficiency on MMTV-ras and MMTV-myc mammary tumor properties.

p21(WAF1/CIP1) (p21) functions as a cyclin-dependent kinase (CDK) inhibitor and is a key mediator of p53-dependent growth arrest. However, its role in cell cycle regulation is complex, because it also appears to promote CDK activity in certain experimental contexts. Its potential role in tumor suppression was evaluated in MMTV-ras and MMTV-myc transgenic mice that were interbred to p21(WAF1/CIP1) knockout mice (p21-/-). p21 deficiency had differential effects on tumor incidence and age of onset, proliferation, and apoptosis in the presence of these two oncogenes. Tumors arising in MMTV-ras/p21-/- mice displayed higher S-phase fractions and correspondingly increased cyclin D1 and E/CDK activity than MMTV-ras tumors. In contrast, MMTV-myc/p21-/- tumors had lower S-phase fractions and levels of cyclin D1 and E/CDK activity than MMTV-myc tumors. In both tumor types, changes in cyclin D1 and E/CDK activity were paralleled by changes in the corresponding cyclin protein levels. Tumor cell apoptosis was also differentially influenced by p21 deficiency in the two models. MMTV-ras/p21-/- tumors exhibited a significant increase in spontaneous apoptosis as compared with MMTV-ras tumors, whereas p21 deficiency had minimal effect on apoptosis in MMTV-myc tumors. These results indicate that the effects of p21 expression on cellular proliferation are differentially affected by the expression of different oncogenes, and that p21 may play a role in promoting either growth arrest or proliferation, depending on the specific cellular context.

Animals↗
PubMed2002

Effect of moderate caloric restriction and/or weight cycling on mammary tumor incidence and latency in MMTV-Neu female mice.

Recently, we reported that intermittent caloric restriction-refeeding reduces mammary tumor (MT) incidence and extends latency in murine mammary tumor virus (MMTV)-transforming growth factor (TGF)-a mice to a greater extent than does chronic caloric restriction. Here, this same weight-cycling protocol was applied to MMTV-Neu female mice, which develop MTs at a much younger age than do TGF-a mice. This study consisted of three experimental groups: mice fed an AIN-93M diet ad libitum, mice intermittently fed an AIN-93 modified diet (2-fold increase in protein, fat, vitamins, and minerals) at 50% of the amount fed to the ad libitum-fed mice for 3-wk intervals and then fed an AIN-93M diet ad libitum for 3-wk intervals, and mice chronically restricted, pair fed to the intermittently restricted mice by feeding 2:1 mixtures of AIN-93M-AIN-93 modified diets for each 6-wk feeding interval. Mice were euthanized when MTs reached a length of 20 mm or at 80 wk of age. Cumulative caloric intake was 10% lower (not significant) for intermittently restricted mice and 16% lower (P < 0.05) for chronically restricted mice than for ad libitum-fed mice. Final body weights were significantly different as follows: ad libitum-fed > intermittently restricted > chronically restricted. Fat pad weights were greater in ad libitum-fed than in intermittently restricted and chronically restricted mice. MT incidence of ad libitum-fed mice was 37% compared with 22% for intermittently restricted mice and 33% for chronically restricted mice (not significant). There were no differences in MT weight or number among the groups. These results indicate that intermittent caloric restriction-refeeding provides a moderate protective effect, whereas chronic caloric restriction provides no significant protection against MT development in transgenic Neu mice.

Adenocarcinoma↗
PubMed1998

Characterization of fatty acid synthase in cell lines derived from experimental mammary tumors.

The lipogenic enzyme fatty acid synthase (FAS) is elevated in various human primary cancers and certain human cancer cell lines. FAS overexpression in human neoplasia has clinical relevance because of its association with tumor aggression and potential chemotherapeutic intervention. Here, we surveyed FAS in cell lines established from normal murine mammary epithelium (NMuMG) and from mammary tumors induced by either rodent polyoma (Py) virus or murine mammary tumor virus (MMTV). Western blotting revealed greater content of FAS in Py-transformed A1-1 and T1 than NMuMG or MMTV-transformed Mm5MT, RIIIMT and MMT060562. These data suggest that signaling events mediated by Py transformation may increase cellular amounts of FAS. Although FAS content was elevated to similar levels in A1-1 and T1, specific activities were significantly different as enzyme activity in T1 was 3-fold higher than A1-1. Likewise, FAS activity in NMuMG was about 0.5-fold higher than the MMTV-transformed lines, even though enzyme content was similar. Immunoprecipitation studies employing anti-phosphoamino acid antibodies followed by immunoblot analysis with anti-FAS antisera (and vice versa) were used to characterize the constitutive phosphorylation state of the enzyme. Phosphoserine and phosphothreonine residues were detected in the more active FAS from T1 and NMuMG, but not in the less active FAS from Mm5MT or A1-1. Discovery of phosphorylated FAS suggests that the enzyme may have more immediate control over lipogenesis than previously thought. High-dose (10-4 M) dexamethasone induced FAS content and activity in NMuMG and MMTV-transformed lines but not Py-transformed cells. Lower concentrations (10-8, 10-6 M) of dexamethasone also activated FAS but without concomitant elevation of its protein content, which was consistent with a phosphorylated form of FAS. Finally, cell lines were treated with the FAS inhibitor cerulenin: almost all breast cancer lines were growth inhibited at significantly lower amounts of drug than normal cell lineages, suggesting that FAS plays a greater role in viability of tumor cells than normal cells. Pretreatment with palmitate (a primary end-product of FAS) prior to cerulenin rescued A1-1 cells only slightly from growth inhibition, whereas pretreatment with oleate (a monounsaturated fatty acid synthesized from palmitate) synergized cerulenin's cytotoxic effects.

Animals↗
PubMed1999

Association of increased radiocurability of murine carcinomas with low constitutive expression of p21(WAF1/CIP1) protein.

PURPOSE: The study investigated whether basal, constitutive levels of p21(WAF1/CIP1) protein in murine carcinomas are related to in vivo tumor radioresponse. The study is based on recent observations demonstrating that in vitro cancer cell lines are resistant to cytotoxic drugs when they express high basal levels of p21(WAF1/CIP1) protein, and that the loss of the p21 gene in the HCT116 human colorectal cancer cell line results in increased radioresponse of xenografts derived from that cell line. METHODS AND MATERIALS: Protein levels of p21(WAF1/CIP1), p53, bax, and bcl-2 were determined in 8 carcinomas (3 mammary carcinomas designated MCa-4, MCa-29, and MCa-35, 2 squamous cell carcinomas designated SCC-IV and SCC-VII, ovarian adenocarcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG) syngeneic to C3Hf/Kam mice using Western blot analysis. The tumors, growing in the right hind legs of mice, were 8 mm in diameter at the time of analysis. These tumors greatly differ in their radioresponse, assessed by TCD50 assay, and in their susceptibility to radiation-induced apoptosis. RESULTS: Protein levels of these oncogenes varied among tumors, with p21(WAF1/CIP1) showing the greatest variation: its mean densitometric value ranged from 1 to 19. Bcl-2 levels also showed broad variation in densitometric values, from 1 to 10. In comparison, bax and p53 (7 of 8 tumors contained wild-type p53) varied much less among different tumor types; their variation was within a 5-fold range, and the level of p53 was similar in 6 of 8 tumors. Tumor radioresponse correlated significantly (R = 0.77, p = 0.02) only with the magnitude of p21(WAF1/CIP1)expression: tumors with high levels of p21(WAF1/CIP1)were less radiocurable than those with lower levels. Tumor radiocurability showed a significant positive correlation (p = 0.02) with the extent of radiation-induced apoptosis, indicating that tumors that responded to radiation with higher percentages of apoptosis were more curable by radiation. Despite a strong trend to correlation, (p = 0.15), p21(WAF1/CIP1) expression did not correlate significantly with radiation-induced apoptosis, which suggested that p21(WAF1/CIP1) influenced tumor radioresponse by mechanisms beyond that of apoptosis induction. CONCLUSION: Our findings showed that murine tumors exhibit wide variation in constitutive levels of p21(WAF1/CIP1) which had a significant relationship with tumor radioresponse: tumors with high levels of p21(WAF1/CIP1) were less radiocurable than those with lower levels. These findings support the concept that p21(WAF1/CIP1) is a major determinant of tumor radioresponse in vivo, and may have important clinical implications. The pretreatment assessment of p21(WAF1/CIP1) protein could serve as a useful predictor of radiotherapy outcome and may assist in selecting an effective treatment modality.

Animals↗
PubMed1996

Induction of cytotoxic T lymphocytes to murine mammary tumor cells with a Kd-restricted immunogenic peptide.

A synthetic peptide E474 SFAVATTAL, derived from the sequence of mouse mammary tumor virus envelope protein, was previously shown to bind class I MHC Kd. Immunization of BALB/c mice with E474 in 50% incomplete Freund's adjuvant (IFA) followed by in vitro stimulation of immune cells with E474-coated antigen-presenting cells resulted in peptide-specific cytotoxic T lymphocytes (CTL). Furthermore, anti-E474 CTL lysed mammary tumor cell lines D2F2 and D2A1, derived from a spontaneous tumor that arose in BALB/c pre-neoplastic hyperplastic alveolar nodule (HAN) D2 line. Expression of Kd by D2A1 and D2F2 cells was verified by flow cytometry, and lysis of D2 tumor cells was blocked by monoclonal antibody 31-34-S, which interacted with the peptide-binding region of Kd, supporting the recognition of E474 in Kd by anti-E474 CTL. Immunization of BALB/c mice with E474 before D2F2 tumor challenge resulted in reduced tumor growth. Therefore, E474 is naturally processed and presented by these tumor cells and can induce anti-tumor immunity.

Amino Acid Sequence↗
PubMed1996

Cysteine concentrations in rodent tumors: unexpectedly high values may cause therapy resistance.

Thiol-containing compounds of low m.w. play a key role in protecting cells from the toxic effects of ionizing radiation, other free-radical-generating reactions, reactive oxygen species and chemical toxins. Previous studies have emphasized the importance of the tripeptide glutathione, which is the most abundant soluble thiol in cells. Cysteine is more difficult to quantitate than glutathione, with reported concentrations only 1-10% that of glutathione in most normal tissues and tissue culture cells. Using an electrochemical method (oxidation of the functional -SH group) which allows the direct assay of thiols after acid extraction of cells or tissue, our measurements confirm the above indicated distribution of glutathione and cysteine in cells and normal tissues. However, in several rat and mouse tumors grown in vivo, we found a much higher proportion of cysteine, sometimes exceeding the millimolar concentrations often found for glutathione. Our results have important implications for predicting tumor radiation resistance since cysteine is a much better radiation-protecting agent than glutathione. Since thiols and oxygen have interacting and opposite effects on the net radiation response, high cysteine levels would directly increase the proportion of radio-resistant cells in tumors.

Animals↗
PubMed1999

Concurrent deregulation of gelsolin and cyclin D1 in the majority of human and rodent breast cancers.

Decreased gelsolin and increased cyclin D1 are among the most common defects found in human and rodent breast cancers. Our purpose was to determine the frequency of concurrence of these 2 alterations in this malignancy. Our results demonstrate that gelsolin protein and mRNA were significantly reduced in 80-100% of rodent mammary carcinomas that developed spontaneously, following oncogene introduction, or after treatment with viral, chemical or hormonal agents. The reduction in gelsolin most likely occurs during the transition from preneoplasia to carcinoma because hyperplasias had normal levels of gelsolin whereas microtumors had reduced expression. Southern analysis revealed no major mutations in the gelsolin gene of tumors with low expression. Cyclin D1 mRNA was increased in 50-100% of these rodent mammary tumors, although the cyclin D1 gene was not amplified. By nuclear runon assay, downregulation of gelsolin in both human and mouse mammary cancer cells involved diminished transcription and, conversely, human breast cancer cells expressing high levels of cyclin D1 had increased initiation of cyclin D1 transcription compared with cyclin D1 low expressors. Thus, alteration in the rate of transcription appears to be an important factor underlying the dysfunction of these genes. According to our data, concurrent deregulation of gelsolin and cyclin D1 is highly prevalent among breast cancers of humans and rodents, with both defects present in 89% of the neoplasms analyzed in this study. In fact, most tumors in every rodent model of mammary tumorigenesis examined had the 2 alterations.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Antibodies to mouse mammary tumor virus-related antigen in sera of patients with breast carcinoma.

Sera from patients with breast carcinoma, benign breast disease, malignancies other than breast carcinoma, and healthy female controls were analyzed by indirect immunofluorescence for the presence of antibodies directed toward antigens of mouse mammary tumor. Sera from 56 to 137 (40.9%) patients with breast carcinoma were positive. Positive reactivity was also found in sera from 5 to 27 (18.5%) patients with benign breast disease, in 7 of 60 (11.7%) patients with malignancies other than breast carcinoma, and in 2 of 56 (3.6%) female controls. In the group of patients with breast carcinoma a correlation was noted between age and the probability of detection of these antibodies. Histopathologic examination of breast cancers indicated that antibodies to antigens in mouse mammary tumors were more often found in patients with infiltrating ductal carcinoma of the mucinous type than with other types of breast tumors. No correlation was demonstrable between the incidence of detection of these antibodies and the stage of the disease. Immunochemical analyses indicated that the antibody activity was present in IgG and IgM classes of immunoglobulins. The human antibodies to antigens in mouse mammary tumors could be removed from patients' sera by absorption with disrupted mouse mammary tumor virus (MMTV) but not with gp52 or gp34 (52,000 and 34,000 dalton polypeptides) of MMTV, or with Rauscher mouse leukemia virus (MLV).

Adult↗
PubMed1991

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.

Animals↗
PubMed1990

The int genes in mouse mammary tumorigenesis and in normal development.

In mice, the mouse mammary tumour virus causes tumours by insertional activation of host cell oncogenes. By the application of transposon tagging techniques, several cellular oncogenes, called int, have been discovered. The int-1 gene encodes a cysteine-rich protein with a signal peptide, suggesting that it may act as an extracellular growth or differentiation factor. Normally, the int-1 gene is expressed in early embryogenesis of the mouse, in particular in the developing nervous system. The essential role of int-1 in embryogenesis is underscored by its high degree of homology with the Drosophila segment polarity gene wingless, a gene involved in pattern formation in segments of the developing fly. In Drosophila, the int-1/wingless gene appears to encode a secreted factor, as concluded from antibody staining experiments. The int-4 gene is not yet fully characterized at the molecular level. From its expression pattern, however, we have concluded that int-4 may also act in the control of embryogenesis: the gene is expressed only during specific time intervals in mouse embryos and it is highly conserved in evolution.

Animals↗
PubMed1987

Morphological characterization of a granulocytosis/hypercalcemia-inducing murine mammary carcinoma cell line.

A newly established cell line of a granulocytosis/hypercalcemia-inducing murine mammary carcinoma (CE mammary carcinoma) grown in serum-free culture medium secretes factors that stimulate proliferation of granulocytes and embryonal bone cells. These cultured cells retain the ability to produce granulocytosis and hypercalcemia when they are transplanted back into mice. In culture these cells form clusters of organized cells. Studies by scanning, transmission, and freeze-fracture electron microscope techniques reveal that these in vitro tumor cells retain the structural epithelial characteristics of mammary epithelia. They maintain cellular polarity, microvilli, and complete tight junctions. Both the in vivo and in vitro tumor cells produce viral particles with the ultrastructural features of murine mammary tumor viruses. In both in vivo and in vitro conditions, A-type particles are present intracellularly. B viral particles are present predominantly in the intercellular spaces. Since the structural characteristics of the cultured tumor cells are consistent with the features of mammary adenocarcinomas, this is a prime culture system for studying the tumor-derived soluble factors.

Animals↗
PubMed1991

Molecular insights into breast cancer from transgenic mouse models.

We desperately need to know more of the biological details of the onset and progression of breast cancer. The disease is of startlingly high incidence (approaching 1 in 9 women), our current therapies for the disease are inadequate once it has metastasized, and the disease is characterized by excessive morbidity and mortality. Most of the growth and differentiation of the mammary gland occurs relatively late in life: during sexual maturation, and then cyclically during pregnancy and lactation. Normal as well as malignant growth is regulated by endocrine hormones as well as by local tissue factors, such as polypeptide growth factors. Cancer seems to progress as hyperplastic ductal or lobular epithelial growth, acquiring progressive genetic changes (including those of oncogenes and tumor suppressor genes) leading to clonal outgrowths of progressively more malignant cells. The nature of proliferative controls and the relevant genetic changes are the subjects of the current review.

Aging↗