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PubMed2000

Transcriptionally regulated adenoviruses for prostate-specific gene therapy.

Most virally based vectors for gene therapy contain viral promoters that are tissue-nonspecific. Consequently, unintended expression of toxic therapeutic genes in normal tissues may potentially occur. We have constructed adenoviruses that contain a bacterial beta-galactosidase (beta-gal) gene (lacZ) under the control of three different prostate-specific promoters: prostate-specific antigen (PSA), probasin, and the mouse mammary-tumor-virus long terminal repeat (MMTV; prostate-specific Ad-lacZ). In general, these prostate-specific Ad-lacZ can effectively transduce and express beta-gal in prostate cells and display weak, if any, expression of beta-gal in nonprostate cells in vitro. In vivo, these adenoviruses showed a high level of beta-gal expression in canine prostate but also disseminated to tissues other than prostate after intraprostatic (i.p.) injection. However, none of the prostate-specific Ad-lacZ expressed beta-gal in these nonprostate tissues. Furthermore, prostate-specific Ad-lacZ expressed beta-gal only in xenograft tumors grown in nude mice, derived from human prostate-cancer cells DU145 and PPC-1, but showed no beta-gal expression in tumors derived from human bladder-cancer cells RT4. These results indicate that adenoviruses containing prostate-specific promoters may express intended transgenes specifically in prostate in vivo.

Adenoviridae↗
PubMed1990

In vitro and in vivo growth and casein gene expression of mouse mammary tumor epithelial cells in response to hormones.

Cells from autochthonous mouse mammary carcinomas which display estrogen-independent growth in vivo were studied for their hormonal responses in primary culture. A culture system employing insulin-supplemented, serum-free medium and basement membrane Matrigel as a substratum was used to cultivate tumor cells. The cells did not exhibit in vitro estrogen- or prolactin-dependent growth. Primary tumors still displayed a constitutional expression of alpha-, beta-, and gamma-casein mRNAs. These messages were dramatically reduced during the culture period. However, seven to eightfold increases in alpha- and beta-casein mRNAs were inducible in the 5-day cultures by treatment with prolactin and hydrocortisone. If the hormones were present through a 2-week culture period, the levels of alpha-, beta-, and gamma-casein mRNAs in the cells were maintained and displayed in a time-dependent increase with a peak at 10-14 days. The accumulation of beta-casein mRNA in vitro did not require DNA synthesis. Administration of prolactin directly into the growing tumors in vivo could also enhance beta-casein mRNA levels in the tumor cells. Morphological studies of the cells cultured in the presence of prolactin and hydrocortisone did not reveal visible changes compared with those without hormonal treatment. Transplantation of tumor cells cultured in the presence or absence of hormones resulted in the development of tumors in mice at approximately the same time. The current studies suggest that the autochthonous mammary tumor cells, independent of estrogen for cell growth, were still inducible for casein gene expression in vitro and in vivo by appropriate hormones. The induction and maintenance of casein messages by a single hormonal treatment did not appear to correlate with morphology and DNA synthesis of cells in vitro or with tumor-producing capacities in vivo.

Adenocarcinoma↗
PubMed2006

Parallel analysis of transcript and translation profiles: identification of metastasis-related signal pathways differentially regulated by drug and genetic modifications.

Tumor metastasis is a complex multistep process normally involving dysregulation of multiple signal transduction pathways. In this study, we developed a novel approach to efficiently define dysreguated pathways associated with metastasis by comparing global gene and protein expressions of two distinct metastasis-suppressed models. Consequently, we identified common features shared by the two models which are potentially associated with metastasis. The efficiency of metastasis from the highly aggressive polyoma middle T-induced mouse mammary tumors was suppressed by either prolonged caffeine exposure or by breeding the animal to a low metastatic mouse strain. Molecular profiles of the primary tumors from both metastasis-suppressed classes were then derived to identify molecules and pathways that might underlie a common mechanism of metastasis. A number of differentially regulated genes and proteins were identified, including genes encoding basement membrane components, which were inversely related to metastatic efficiency. In addition, the analysis revealed that the Stat signal transduction pathways were potentially associated with metastasis inhibition, as demonstrated by enhanced Stat1 activation, and decreased Stat5 phosphorylation in both genetic and pharmacological modification models. Tumor cells of low-metastatic genotypes also demonstrated anti-apoptotic properties. The common changes of these pathways in all of the metastasis-suppressed systems suggest that they may be critical components in the metastatic cascade, at least in this model system. Our data demonstrate that analysis of common changes in genes and proteins in a metastatic-related context greatly decrease the complexity of data analysis, and may serve as a screening tool to identify biological important factors from large scale data.

Animals↗
PubMed1976

Preneoplastic lesions in murine mammary cancer.

The current model for murine mammary tumorigenesis indicates that discrete, morphologically identifiable preneoplastic lesions precede and give rise to mammary tumors. The hyperplastic alveolar nodule is the primary lesion that precedes and gives rise to mammary tumors in mice infected with the mammary tumor virus (Bittner) or its variants. In mice fed 7,12-dimethylbenzanthracene or urethan, hyperplastic alveolar nodules are present but infrequent, and the major mammary dysplasias present are ductal hyperplasias. The ductal hyperplasias can be divided into four general morphological types: (a) simple terminal duct hyperplasia; (b) lobular hyperplasia; (c) papillary hyperplasia; (d) end-bud hyperplasia. All types of ductal hyperplasias are characterized by intraductal epithelial hyperplasia and have been shown to give rise to mammal adenocarcinomas in situ or by transplantation into the mammary gland-free fat pads of syngeneic mice. Our current hypothesis is that murine mammary cancer can evolve through one of several intermediate stages. The intermediate stages can be either alveolar or ductal hyperplasias. The latter resemble, in many instances, ductal lesions seen in human breast cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Differences in progression of BALB/cfRIII and BALB/cfC3H mammary hyperplastic alveolar nodules transplanted into the gland-free fat pads of BALB/c mice.

In BALB/cfC3H and BALB/cfRIII virgin female mice, i.e., BALB/c mice carrying milk-transmitted C3H and those carrying RIII murine mammary tumor virus infection, respectively, mammary noduligenesis and tumorigenesis are remarkably different. Focal hyperplastic alveolar changes or hyperplastic alveolar nodules were removed from BALB/cfRIII or BALB/cfC3H breeding female donors and transplanted into the gland-free mammary fat pads of syngeneic BALB/c virgin female recipients with or without hormonal supplementation. The results obtained have shown significant differences in: (a) the morphological type of outgrowths; (b) the incidence of malignant transformations; and (c) the hormonal responsiveness of the tumors arisen after pituitary transplants.

Adipose Tissue↗
PubMed1977

Bioactivity of C3H and RIII mammary tumor viruses in virgin female BALB/c mice.

The bioactivities of C3H and RIII mammary tumor virus (MuMTV) in virgin female BALB/c mice differed. The average number of mammary hyperplastic alveolar nodules per mouse after noduligenic tests was 20.1 in BALB/cfC3H and 10.7 in BALB/cfRIII females. Spontaneous mammary tumor incidence after 20 months of observation was 47.5% in BALB/cfC3H and 14.6% in BALB/cfRIII females (P less than 0.01). The frequency of lung metastases in mammary tumor-bearing mice was 63.1% in BALB/cfC3H and 16.6% in BALB/cfRIII females (P less than 0.05), although the clinical duration of mammary tumors was the same. These data demonstrated a lower bioactivity of RIII MuMTV when compared to C3H MuMTV in BALB/c mice and suggested that the causative virus may control all the steps of mouse mammary tumor development, including metastasis.

Animals↗
PubMed1993

Inhibitory effect of Bifidobacterium longum on colon, mammary, and liver carcinogenesis induced by 2-amino-3-methylimidazo[4,5-f]quinoline, a food mutagen.

The inhibitory effect of lyophilized cultures of Bifidobacterium longum on 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced carcinogenesis was investigated in male and female F344 rats. Beginning at 5 weeks of age, male and female rats were divided into various experimental groups and fed one of the high-fat, semipurified diets containing 0 and 0.5% lyophilized cultures of B. longum with or without 125 ppm IQ in the diet. All animals were continued on this regimen until the termination of the study. All animals were necropsied during the 58th week. The results indicated that dietary B. longum significantly inhibited the IQ-induced incidence (percentage of animals with tumors) of colon (100% inhibition) and liver (80% inhibition) tumors and multiplicity (tumors/animal) of colon, liver, and small intestinal tumors in male rats. In female rats, dietary supplementation of Bifidobacterium cultures also suppressed the IQ-induced mammary carcinogenesis to 50% and liver carcinogenesis to 27% of those observed in animals fed the control diet, but the differences did not reach a statistical significance at P < 0.05; however, the mammary tumor multiplicity (tumors/animal) was significantly (P < 0.05) inhibited in female rats fed the diet containing Bifidobacterium cultures. These findings suggest that Bifidobacterium supplements in the diet inhibit IQ-induced colon and liver tumors and to a lesser extent mammary tumors in F344 rats.

Animals↗
PubMed1992

Early and multifocal tumors in breast, salivary, harderian and epididymal tissues developed in MMTY-Neu transgenic mice.

Transgenic mice carrying various oncogenes driven by mammary gland specific enhancers develop mammary tumors usually arising in a stochastic way. The only exception is a mouse lineage (TG.NF) carrying an activated rat Neu oncogene driven by the murine mammary tumor virus long terminal repeat (MMTV-LTR) that gave rise to rapid and multifocal mammary tumors interpreted as a result of a single-step neoplastic transformation. The effect of the oncogene appeared to be specific for breast tissue, since salivary and Harderian glands as well as epididymis expressed high levels of Neu but only developed hyperplasia (Muller et al., Cell, (1988) 54, p. 105). Here we describe a transgenic mouse lineage for the MMTV-Neu, analysed up to third generation. Multifocal tumors involving mammary glands arose very rapidly in all females independently from pregnancy and in some males. Moreover, multifocal neoplasias occurred also in salivary and Harderian glands and in the epididymis at a very high rate. These data demonstrate that the Neu oncogene can induce tumors in all the tissues where it is expressed at high levels.

Animals↗
PubMed1985

Nucleotide sequence and expression in vitro of cDNA derived from mRNA of int-1, a provirally activated mouse mammary oncogene.

The mouse int-1 gene is a putative mammary oncogene discovered as a target for transcriptionally activating proviral insertion mutations in mammary carcinomas induced by the mouse mammary tumor virus in C3H mice. We have isolated molecular clones of full- or nearly full-length cDNA transcribed from int-1 RNA (2.6 kilobases) in a virus-induced mammary tumor. Comparison of the nucleotide sequence of the cDNA clones with that of the int-1 gene (A. van Ooyen and R. Nusse, Cell 39:233-240, 1984) shows the following. The coding region of the int-1 gene is composed of four exons. The splice donor and acceptor sites conform to consensus; however, at least two closely spaced polyadenylation sites are used, and the transcriptional initiation site remains ambiguous. The major open reading frame is preceded by an open frame 10 codons in length. The mRNA encodes a 41-kilodalton protein with several striking features--a strongly hydrophobic amino terminus, a cysteine-rich carboxy terminus, and four potential glycosylation sites. There are no differences in nucleotide sequence between the known exons of the normal and a provirally activated allele. The length of the deduced open reading frame was further confirmed by in vitro translation of RNA transcribed from the cDNA clones with SP6 RNA polymerase.

Animals↗
PubMedDate not supplied

Normal and neoplastic mammary gland growth in MMTV/TGF alpha transgenic mice.

Biochemical and Dynamic change of mammary glands in different reproductive states were studied in comparison with histological structures in female and male transgenic mice bearing human transforming growth factor alpha (TGF alpha) cDNA under the control of the mouse mammary tumour virus enhancer/promoter. Female and male F1 mice between SHN female and transgenic male mice were divided into TGF alpha (+) and TGF alpha (-) groups according to the presence of TGF alpha gene at approximately 50 days of age. While there was little difference in mammary gland contents of DNA and RNA in females at 2 months of age, both nucleic acid contents were elevated markedly in TGF alpha (+) female mice with large variations at 4 months. These extremely high DNA and RNA contents in the TGF alpha (+) group declined to the level of the TGF alpha (-) group in the middle of pregnancy and at the end of pregnancy, respectively. Thymidine kinase (TK) activity in the mammary glands as an index of DNA synthesis was significantly higher in TGF alpha (+) mice than in TGF alpha (-) mice at both 2 and 4 months of age and the high TK in TGF alpha (+) mice also declined to the level of TGF alpha (-) mice with pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Proviral insertions within the int-2 gene can generate multiple anomalous transcripts but leave the protein-coding domain intact.

We examined the effects of mouse mammary tumor virus integration on the multiple RNA transcripts expressed from the int-2 proto-oncogene in virally induced breast tumors. Proviral insertion either upstream or downstream of the gene could simultaneously activate transcription from three dissimilar int-2 promoters. In some tumors, the activating provirus lies within the transcription unit and disrupts the structures of the various RNAs. Insertions in the 5' region of the gene had complex effects depending on the orientation and position of the provirus relative to the three promoters and intron-exon boundaries. RNase protection experiments identified transcripts initiated in the viral long terminal repeat, at normal and cryptic sites in the int-2 sequences, and from cryptic promoters in an inverted provirus. AT the 3' end, insertions occurred within the untranslated trailer and provided alternative termination signals that substituted for one or both of the normal the poly(A) addition sites. However, in no instance, of the 20 tumors analyzed in detail, did a provirus perturb the presumed open reading frame of the gene. These data strongly implicate the normal product of the int-2 gene, which is related to the fibroblast growth factor family, as a contributory factor in virally induced mammary tumors.

Animals↗
PubMed1995

Int-6, a highly conserved, widely expressed gene, is mutated by mouse mammary tumor virus in mammary preneoplasia.

With a unique mouse mammary tumor model system in which mouse mammary tumor virus (MMTV) insertional mutations can be detected during progression from preneoplasia to frank malignancy, including metastasis, we have discovered a new common integration site (designated Int-6) for MMTV in mouse mammary tumors. MMTV was integrated into Int-6 in a mammary hyperplastic outgrowth line, its tumors and metastases, and two independent mammary tumors arising in unrelated mice. The Int-6 gene is ubiquitously expressed as a 1.4-kb RNA species in adult tissues and is detected beginning at day 8 of embryonic development. The nucleotide sequence of Int-6 is unrelated to any of the known genes in the GenBank database. MMTV integrates within introns of the gene in the opposite transcriptional orientation. In each tumor tested, this results in the expression of a truncated Int-6/long terminal repeat (LTR) chimeric RNA species which is terminated at a cryptic termination signal in the MMTV LTR. Since the nonrearranged Int-6 alleles in these tumors contain no mutations, we favor the conclusion that truncation of the Int-6 gene product either biologically activates its function or represents a dominant-negative mutation.

Amino Acid Sequence↗