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At least 613 records · Page 34Linked to original sources
PubMed2003

Introduction of estrogen receptor-alpha into the tTA/TAg conditional mouse model precipitates the development of estrogen-responsive mammary adenocarcinoma.

Conditional expression of estrogen receptor (ER)-alpha) was introduced into tetracycline-responsive MMTV-tTA/tetop-TAg mice to develop a mouse model of estrogen-responsive ER-alpha-positive mammary adenocarcinoma. Mammary adenocarcinomas developed in the mice with a mean latency of 11 months. Precursor lesions including ductal hyperplasia and hyperplastic alveolar nodules were present by the age of 4 months. The mammary adenocarcinomas exhibited histological features similar to human breast cancers. ER steroid-binding studies conducted on adenocarcinoma lysates demonstrated binding to estradiol. Tumor explant studies in the presence and absence of estradiol in ovariectomized athymic nude mice revealed that growth of mammary tumors was stimulated by estrogen. In addition, the presence of ER-alpha altered the tumor spectrum in other MMTV-targeted tissues in the tTA/TAg female mice. Lymphomas, which develop in 40% of tTA/TAg female mice, were found in only 4% of tTA/TAg/ER-alpha mice (P = 0.014, chi-square test). These experiments demonstrate that the introduction of an ER-alpha transgene targeted to mammary epithelial cells can be used to develop mouse models of ER-alpha-responsive mammary cancer.

Adenocarcinoma↗
PubMed2002

Acceleration of mouse mammary tumor virus-induced murine mammary tumorigenesis by a p53 172H transgene: influence of FVB background on tumor latency and identification of novel sites of proviral insertion.

We previously showed that a mammary-specific dominant-negative p53 transgene (WAP-p53(172H)) could accelerate ErbB2-induced mammary tumorigenesis in mice, but was not tumorigenic on its own. To identify other genes that cooperate with WAP-p53(172H) in tumorigenesis, we performed mouse mammary tumor virus (MMTV) proviral mutagenesis. We derived F1, N2, and N4/N5 mice from p53(172H) transgenic FVB mice backcrossed onto MMTV+ C3H/He mice. Results show the latency of MMTV tumorigenesis is correlated with FVB contribution. F1 tumors had the shortest latency (217 days), had a higher rate of metastasis, and were less differentiated than the N2 and N4/N5 tumors. The latency was 269 days in N2 mice, and lengthened to 346 days in N4/N5 mice. p53(172H) significantly accelerated MMTV tumorigenesis only in N2 mice, indicating cooperativity between p53(172H) and MMTV in this cohort. To identify genes that may be causally involved in MMTV-induced mammary tumorigenesis, we identified 60 sites of proviral insertion in the N2 tumors. Among the insertions in p53(172H) transgenic tumors were 10 genes not previously found as sites of MMTV insertion including genes involved in signaling (Pdgfra, Pde1b, Cnk1), cell adhesion (Cd44), angiogenesis (Galgt1), and transcriptional regulation (Olig1, Olig2, and Uncx4.1). These may represent cellular functions that are likely not deregulated by mutation in p53.

Animals↗
PubMed1999

Development of hyperplasias, preneoplasias, and mammary tumors in MMTV-c-erbB-2 and MMTV-TGFalpha transgenic rats.

Human cDNAs corresponding to two epidermal growth factor-related products that are overexpressed in human breast cancers, that for c-erbB-2 (HER-2) and for transforming growth factor alpha (TGFalpha), have been cloned downstream of the mouse mammary tumor virus (MMTV) long terminal repeat promoter and injected into the pronucleus of fertilized oocytes of Sprague-Dawley rats to produce transgenic offspring. Expression of the transgenic mRNAs is not detectable in mammary tissue from virgin transgenic rats but is detected in mammary tissue from certain lines of mid-pregnant transgenic rats. When two such lines of either type of transgenic rat are subjected to repeated cycles of pregnancy and lactation, they produce, primarily in the mammary glands, extensive pathologies, whereas virgin transgenic rats produce no such abnormalities. Multiparous transgenic female offspring from c-erbB-2-expressing lines develop a variety of focal hyperplastic and benign lesions that resemble lesions commonly found in human breasts. These lesions include lobular and ductal hyperplasia, fibroadenoma, cystic expansions, and papillary adenomas. More malignant lesions, including ductal carcinoma in situ and carcinoma, also develop stochastically at low frequency. The mammary glands of transgenic females invariably fail to involute fully after lactation. Similar phenotypes are observed in female MMTV-TGFalpha transgenic rats. In addition, multiparous TGFalpha-expressing female transgenics frequently develop severe pregnancy-dependent lactating hyperplasias as well as residual lobules of hyperplastic secretory epithelium and genuine lactating adenomas after weaning. These transgenic rat models confirm the conclusions reached in transgenic mice that overexpression of the c-erbB-2 and TGFalpha genes predisposes the mammary gland to stochastic tumor development.

Animals↗
PubMed1992

Androgen-responsive expression and mitogenic activity of schwannoma-derived growth factor on an androgen-dependent Shionogi mouse mammary carcinoma cell line.

We report here, using the androgen-dependent SC2G cell line derived from Shionogi mouse mammary carcinoma SC115, that cDNA encoding mouse homologue of the rat schwannoma-derived growth factor (SDGF) was isolated and its protein product was identified to be an autocrine growth factor which is expressed in response to androgen in this hormone-dependent cell line. The androgen-independent SC1G cells derived from SC115 were shown to express SDGF even in the absence of androgen, while Northern analysis probed with mouse mammary tumor virus (MMTV) DNA showed that the androgen inducible transcriptional machinery remains functional in this hormone independent cell line.

Amino Acid Sequence↗
PubMed1980

Synthesis and biological activity of some 1-N-substituted 2-acetamido-2-deoxy-beta-D-glycopyranosylamine derivatives and related analogs.

Several 1-N-substituted derivative [haloacetyl-, glycyl-, (dimethyl)amino-acetyl-, azidoacetyl-, trifluoroacetyl-, and trifluoromethylsulfonyl-] of 2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-beta-D-glucopyranosylamine (1) were synthesized as potential metabolic inhibitors of cellular-membrane glycoconjugates. Several fully acetylated derivatives were found to inhibit growth of mouse mammary adenocarcinoma TA3, leukemia L1210, or leukemia P-288 cells at 1-0.01 mM concentration in vitro. Some of these derivatives were less active after O-deacetylation. Analogs of 1 in which NH2-1 was replaced by OH- or OAc-1 were also active on the same cell systems. The growth-inhibitory activity was correlated with inhibition of the incorporation of 2-amino-deoxy-D-glucose and L-leucine into a macromolecular fraction.

Acetylglucosamine↗
PubMed2003

Mouse mammary tumor viruses expressed by RIII/Sa mice with a high incidence of mammary tumors interact with the V beta-2- and V beta-8-specific T cells during viral infection.

The mouse mammary tumor viruses (MMTVs) that induce mammary adenocarcinomas in mice are transmitted from mother to offspring through milk. MMTV infection results in the deletion of specific T cells as a consequence of interaction between the MMTV-encoded superantigen (Sag) and specific V beta chains of the T cell receptor. The specificity and kinetics of T cell deletion for a number of highly oncogenic MMTVs, such as C3H- and GR-MMTVs, have been studied in great detail. Some work has also been done with the MMTVs expressed in two substrains of RIII mice, BR6 and RIIIS/J, but the nature of the interaction between T cells and the virus(es) that the parental RIII-strain of mice express has not been investigated. Since RIII mice (designated henceforth as RIII/Sa) have a very high incidence (90-98%) of mammary tumors, and they have been extensively used in studies of the biology of mammary tumor development, we have presently determined the pattern of V beta-T cell deletion caused by RIII/Sa-MMTV-Sag(s) during viral infection. T cells were isolated from lymph nodes and thymus of young RIII/Sa mice, as well as from BALB/c (BALB/cfRIII/Sa), C57BL (C57BLfRIII/Sa), and RIIIS/J (RIIIS/JfRIII/Sa) mice after they were infected with RIII/Sa-MMTV(s) by foster nursing. The composition of the T cells was analyzed by FACS using a panel of monoclonal antibodies specific to a variety of V betas. Our results show that milk-borne RIII/Sa-MMTV(s) infection leads to the deletion of CD4(+) V beta-2, and to a lesser extent V beta-8 bearing peripheral and central T cells in RIII/Sa, RIIIS/J, BALB/c, and C57BL mice. Our results are in contrast to the findings that C3H-, GR-, and BR6-MMTVs delete V beta-14- and/or V beta-15-specific T cells.

Amino Acid Sequence↗
PubMed2002

Mammary stem cell repertoire: new insights in aging epithelial populations.

The proliferative lifespan of mammary stem cells was examined in serially transplanted clonal-dominant epithelial populations. Five successive transplant generations were done. The epithelial cell number in each outgrowth expands approximately 500-fold in nulliparous hosts and approximately 10000-fold in impregnated hosts. Despite this, all resulting mammary outgrowths showed lineal identity with the original. Growth senescence was observed in some implants beginning at the third generation in impregnated recipients. The ability of an individual implant to support ductal morphogenesis and also secretory lobule development decayed at independent rates. Individual implants from a single clonal-dominant outgrowth occasionally gave rise to markedly different ductal development within the same host indicating an epithelial cell autonomous mechanism in ductal patterning. Both premalignant and malignant populations appeared focally within the aging transplants. These populations were also lineally related to the original outgrowth supporting the conclusion that the primary growth was derived clonally from one or a few lineally related antecedents. The premalignant and malignant descendant populations no longer exhibit growth senescence suggesting that they are supported by a perpetually self-renewing progenitor. Our evidence indicates that a single mammary cell may have the capacity to self-renew through five transplant generations. Even some sixth generation implants show vigorous growth.

Animals↗
PubMed1984

Protoneoplasia: the molecular biology of murine mammary hyperplasia.

The mouse mammary tumor virus has provided a window into the inner workings of the mammary epithelial cell at the earliest stages of neoplasia. Techniques of molecular biology permitted us to look through that window revealing a new biology which deserves consideration as a model for mammary tumorigenesis in all species. According to this model the neoplastic process originates in a single mammary epithelial cell as a result of a critical genetic alteration, such as integration of MuMTV (MuMHV) into a key site in the mouse genome (Fig. 4). The genetic alteration immortalizes the cell and provides it with selective growth advantages which result in a clonal proliferation. This original proliferation emerges as the protoneoplastic mammary hyperplasia. The protoneoplastic cells have limited growth potential and are not obligated to undergo malignant transformation but they represent a genetically evolving population highly susceptible to full blown malignancy after exposure to carcinogens. Protoneoplastic cells which undergo further genetic alterations that provide additional selective growth advantages proliferate and emerge as malignant tumors. The genetic alterations are sometimes reflected by changes in viral DNA but this is not essential and most mouse mammary tumors probably do not occur as the result of new host-virus interactions. No doubt the current work on the mouse "int" loci will help define the genes responsible for the induction and maintenance of the protoneoplastic state. Since such host genes have proven so ubiquitous, one must also predict that analogous genes will be found in human mammary protoneoplasias. Detection of such sequences may help distinguish protoneoplastic processes from nonneoplastic, low risk hyperplasias in the human breast. Finally, the gene or genes involved in the more lethal malignant transformation await elucidation. Based on past and current progress one can be sure that the mouse mammary tumor system will help point the way.

Animals↗
PubMed1980

Methylation of milk-borne and genetically transmitted mouse mammary tumor virus proviral DNA.

The 5-methylcytosine content of mouse mammary tumor virus (MMTV)-specific DNA sequences acquired by both milk-borne infection and genetic transmission was determined for both normal and neoplastic tissues of the mouse. Using the restriction endonuclease Msp I, which cleaves at the recognition sequence 5'-CCGG, and its isoschizomer Hpa II, which is inhibited by methylation of the cytosine base of the CpG dinucleotide, it can be demonstrated that MMTV proviruses acquired via germ line infection are extensively methylated at both the site for Msp I-Hpa II cleavage and the site for Hha I (5'-GCGC), which is also inhibited by base modification of the cytosine. The virus-specific sequences acquired via milk-borne infection, however, are not modified at these sites in DNA from either normal infected or transformed tissues. Finally, cellular sequences are nonspecifically hypomethylated in a phenomenon unique to transformed tissue and apparently unrelated to the specific hypomethylation of exogenously acquired MMTV proviruses.

5-Methylcytosine↗
PubMed1997

Long-term feeding of field bean protein containing protease inhibitors suppresses virus-induced mammary tumors in mice.

Protease inhibitors (PIs) of synthetic, bacterial or soybean origin have been shown to suppress carcinogen or radiation-induced rat mammary carcinogenesis. We report, for the first time, the effect of year-long feeding of Field bean meal, a rich source of PIs with a 24% protein content, at different protein levels in the diet, on mouse mammary tumor virus (MMTV)-induced mammary tumorigenesis in C3H/Jax mice. Weanling female mice were randomized and divided into groups and fed chow or chow with 2%, 4%, 8% FB protein (FBP) or autoclaved 2% FBP (AFBP) until 49 weeks and the incidence of mammary tumors was recorded until 58 weeks when they were sacrificed. Mice fed 2% FBP showed significant (P < 0.001) reduction (68%) in tumor incidence and delay (P < 0.02) in tumor appearance compared to controls. This suppressive effect on mammary tumorigenesis increased with increased FBP intake with values of tumor suppression being 75% and 81% in mice groups fed 4% and 8% FBP, respectively. Incidentally, the tumors appeared earlier (P < 0.05) in the 8% FBP-treated mice compared to other groups. Moreover, this suppressive effect on mammary tumorigenesis was related to the PI activity of the FB meal, since mice fed 2% AFBP showed no reduction in tumor incidence. Heat treatment, which had destroyed the PI activity, apparently did not affect other chemopreventive agents known to be present in plant material. This possibility is supported by our observation that prolonged feeding of 2% FBP or 2% AFBP increased the liver glutathione content of mice, suggesting the presence of a highly heat-stable factor, other than PIs, in the FBP, which brought about this elevation. Further, while 2% or 4% FBP- and 2% AFBP- treated mice showed no adverse growth effects, only the 8% FBP-fed group showed a significant lower growth curve compared to control mice, with some of them showing pancreatic lesions.

Animals↗
PubMed1998

Possible retroviral etiology of human breast cancer.

Since the discovery in the early 1980s that retroviruses are pathogenic to man, the mouse mammary tumor viruses (MMTVs) received great attention. Studies of MMTVs allowed considerable insights into the mechanisms at work in breast tumorigenesis. MMTVs are essentially insertional mutagenes. Numerous oncogenes have been found altered by MMTVs, either specific for MMTVs or not. However, despite considerable attempts, the involvement of MMTVs in human breast cancer remains questionable. Yet a retroviral etiology of human breast cancer cannot be discarded since retroviruses are good candidates to play a role in diseases which, like human breast cancer, appear either as sporadic or inherited. Due to their replication cycle, retroviruses can be propagated not only as infectious agents able to freely infect host cells, but also as cellular genes which can be passed on to progeny. It is suggested here to search for a new human retrovirus in sporadic breast cancer, using the techniques which led to the isolation of human T-cell leukemia virus-1 (HTLV-1). Indeed, finding an infectious retrovirus in sporadic cases could lead, via the c-DNA probes derived from it, to testing the hypothesis that the inherited form of human breast cancer may result from the action of retroviral genes integrated in the germ line.

Animals↗