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At least 235 records · Page 13Linked to original sources
PubMed1996

Keratinocyte growth factor induces mammary and prostatic hyperplasia and mammary adenocarcinoma in transgenic mice.

The kinetics of solitary mammary tumor formation in transgenic mice bearing the MMTV-int-2 (fgf3) fusion gene suggest that several genetic events are required for tumorigenesis. In an effort to identify elements that could contribute to this oncogenic process, we used differential display PCR to identify gene products that are strongly and specifically induced in int-2 mammary tumors. Using this approach we identified a member of the FGF family, kgf (fgf7), as a gene that is strongly upregulated in an int-2-containing mammary tumor. Since int-2 and kgf strongly bind the same receptor, the IIIb isoform of FGFR2, it is possible that their joint expression, one as a transgene, the other as an activated gene, might reinforce the same mitogenic pathway. To test this possibility, we created transgenic mice that carry kgf as a transgene gene under the control of the MMTV promoter/enhancer. Female mice carrying this transgene develop a very dramatic mammary epithelial hyperplasia and go on to develop solitary, metastatic adenocarcinomas of the mammary gland. Consistent with a common signalling pathway, the MMTV-kgf-induced hyperplasia has the morphologic characteristics of that seen in the MMTV-int-2 mice. Male mice also develop hyperplasia of the male genital tract, including the seminal vesicle, the vas deferens and the prostate. Thus KGF can act as a potent proliferative inducer in mammary and specific urogenital tissue and can contribute to the development of adenocarcinoma of the mammary gland in a manner strongly reminiscent of receptor-related ligand, int-2.

Age Factors↗
PubMed1986

Consequences of widespread deregulation of the c-myc gene in transgenic mice: multiple neoplasms and normal development.

We have constructed a transgenic mouse strain in which a mammary tumor virus LTR/c-myc fusion gene is anomalously expressed in a wide variety of tissues. The deregulated c-myc transgene, now glucocorticoid inducible, contributes to an increased incidence of a variety of tumors, including those of testicular, breast, lymphocytic (B cell and T cell), and mast cell origin. The deregulated gene does not, however, otherwise disturb cell proliferation, nor does it interfere with normal development in these animals. Moreover, since not all tissues that express the transgene develop neoplasms, these results begin to define the transforming spectrum of the c-myc oncogene. They also extend to several organ systems the notion that elements in addition to an activated c-myc gene are required to induce malignancy in the living organism.

Adenocarcinoma↗
PubMed1980

DNA binding and unwinding activities associated with intracytoplasmic a particles isolated from mouse mammary tumors.

Intracytoplasmic A particles (CAP), previously identified as probably cytoplasmic nucleocapsid precursor structures to mouse mammary tumour virus (MMTV), possess both DNA binding and DNA unwinding activities, CAP proteins bind to both single-stranded (ss)- and double-stranded (ds)DNA, with the ssDNA slightly preferred. This activity was linear over a 30-fold concentration of A particle protein and was not affected by NaCl concentrations as high as 0.6 M or pH changes over a wide range. DNA binding by CAP proteins was sensitive to heat or addition of sodium dodecyl sulphate (SDS) and was neutralized by pre-incubation of CAP with anti-MMTV p14, but not by anti-MMTV p27, p10 or anti-mouse casein. Incubation of CAP with dsDNA led to unwinding of the double helix as measured by its increased sensitivity to S1 nuclease digestion. This activity was also linear over a several-fold concentration of A particle protein and was heat labile. It was not inhibited by pre-incubation of CAP with either anti-MMTV p14 or with anti-MMTV, anti-MMTV p27 and anti-MMTV p10. DNA unwinding was inhibited by anti-A particle antiserum and to a lesser extent by anti-CAP p20-18.

Animals↗
PubMedDate not supplied

Studies of mammary carcinoma metastasis in a mouse model system. I: Derivation and characterization of cells with different metastatic properties during tumour progression in vivo.

The biological and metastatic properties of cells from a murine mammary adenocarcinoma, MT1, were studied during serial transplantation in syngeneic hosts. Over 35 generations the tumour progressed from a well-differentiated, poorly metastatic neoplasm to an anaplastic highly metastatic state. At early passages the tumour yielded uniform cultures of cuboidal epithelial cells, at passage 17 both epitheloid and spindle type cells were present, and by passage 30 only spindle type cells were obtained. Epithelioid cell lines and clones when injected intravenously into syngeneic hosts produced lung colonies only, whereas spindle cell lines were capable of extensive extrapulmonary colonisation. Similar patterns of dissemination and growth were seen in spontaneous metastasis assays. In spite of the marked phenotypic differences in these 'subpopulations', their comparable ultrastructural features, oestrogen receptor levels, expression of MMTV antigens, DNA content and lectin binding profiles suggested a common cell lineage. It is proposed that these cell lines will be of use in the determination of tumour and host factors influencing tumour progression and the evolution of metastatic potential.

Animals↗
PubMed1992

The pathobiology of salivary gland. II. Morphological evaluation of acinic cell carcinomas in the parotid gland of male transgenic (MMTV/v-Ha-ras) mice as a model for human tumours.

In the transgenic TG.SH (mouse mammary tumour virus/v-Ha-ras) mouse, designed to develop mammary tumours, occasional spontaneous salivary gland tumours have been reported, predominantly in males. The incidence and histomorphology of salivary gland tumours in 73 TG.SH mice were surveyed and in total, 21.9% developed both overt and microscopic parotid tumours. The majority developed between 73 and 150 days of age. In 31.5% of the TG.SH mice, occasional unilateral, but more frequently bilateral exophthalmos due to hyperplasia of the intraorbital (Harderian) lacrimal gland was observed. In 70% of these animals, parotid tumours developed later. Since Harderian gland hyperplasia, occurring as early as 5 weeks of age, preceded the development of palpable salivary gland lesions, this stigma is useful for the early selection of animals likely to progress to tumour formation. Before tumour-bearing transgenic mice are considered to be suitable models of human neoplastic disease, morphological characterization is necessary to ensure that the tumours are histologically representative of the human lesions for which they are potential models. In this study, all parotid tumours consisted of acinar-like glandular structures with central lumina discernible by electron microscopy. Ultrastructurally, secretory granules evident in the apical cytoplasm of the tumour cells resembled the zymogen granules of the normal parotid acinar cell, and some cells had a prominent complement of rough endoplasmic reticulum. These features, along with focal amylase expression detected immunohistochemically in some parotid tumours, identified these neoplasms as acinic cell carcinomas that mimic the human salivary gland acinic cell carcinoma faithfully.

Animals↗
PubMed1983

Effect of malignant transformation upon the cellular retinoid binding proteins in cultured murine mammary cells.

Cellular retinol (CRBP) and retinoic acid binding proteins (CRABP) were measured in normal (C57Bl) and Murine Mammary Tumor Virus (MuMTV)-induced murine mammary tumor cells (C57BlfRIII) grown in monolayer culture. High speed supernatant fractions (cytosols) from transformed cells contained elevated levels of CRBP and CRABP (0.276 and 1.410 pmol/mg protein, respectively) compared to cytosol from non-transformed murine mammary cells which contained only low levels of CRBP (0.099 pmol/mg protein). Our findings suggest that malignant transformation of mammary epithelial cells, induced by MuMTV infection, results in changes in the expression of cellular retinoid binding proteins and possibly in the sensitivity of these cells to various retinoids.

Animals↗
PubMed2001

Mammary epithelial-specific expression of the integrin-linked kinase (ILK) results in the induction of mammary gland hyperplasias and tumors in transgenic mice.

The integrin linked kinase (ILK) is a cytoplasmic effector of integrin receptors, involved in the regulation of integrin binding properties as well as the activation of cell survival and proliferative pathways, including those involving MAP kinase, PKB/Akt and GSK-3beta. Overexpression of ILK in cultured intestinal and mammary epithelial cells has been previously shown to induce changes characteristic of oncogenic transformation, including anchorage-independent growth, invasiveness, suppression of anoikis and tumorigenicity in nude mice. In order to determine if ILK overexpression can result in the formation of mammary tumors in vivo, we generated transgenic mice expressing ILK in the mammary epithelium, under the transcriptional control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). By the age of 6 months, female MMTV/ILK mice developed a hyperplastic mammary phenotype, which was accompanied by the constitutive phosphorylation of PKB/Akt, GSK-3beta and MAP kinase. Focal mammary tumors subsequently appeared in 34% of the animals at an average age of 18 months. Given the focal nature and long latency of the tumors, however, additional genetic events are likely required for tumor induction in the MMTV/ILK mice. These results provide the first direct demonstration of a potential oncogenic role for ILK, which is upregulated in human tumors and tumor cell lines.

Adenocarcinoma, Papillary↗
PubMed1976

Plasma levels of a viral protein as a diagnostic signal for the presence of tumor : the murine mammary tumor model.

We used the mouse mammary tumor and its associated virus (murine mammary tumor virus) to examine the possibility of using plasma levels of a viral protein (gp52, the glycoprotein of 52,000 molecular weight) as a diagnostic indicator of the presence of a solid tumor. The following features have emerged from our studies: (a) tumor-bearing animals show markedly elevated (100-1000 ng/ml) plasma levels of gp52 and the mean concentration increases with tumor size; (b) mammary tumor tissues located outside the mammary gland are also detected by the elevated plasma gp52; (c) low (2-10 ng/ml) plasma levels of gp52 are found in tumor-free mice, whether they are derived from strains characterized by high or low frequencies of spontaneous mammary tumors; (d) tumor-free lactating females exhibit the normally low levels of plasma gp52 despite the fact that their milk contains an average of 20,000 ng/ml of this antigen; (e) thus, high levels of plasma gp52 are found only in the presence of tumor and are not induced by either predisposition for the disease or by normal production of the antigen during lactation; (f) the circulatory clearance time of gp52 is sufficiently rapid to require continued replenishment to maintain the high levels observed in tumor-bearing animals, a feature implying that the gp52 concentration can be a responsive parameter of disease status. The information obtained suggests that plasma gp52 is a potentially useful and specific systemic indicator of the presence and extent of murine mammary neoplasia.

Animals↗
PubMed1987

Tenascin is a stromal marker for epithelial malignancy in the mammary gland.

Tenascin is an extracellular matrix glycoprotein that is not present in the normal mature rat mammary gland. The distribution of tenascin was examined by immunohistochemistry in mammary tumors from carcinogen-treated and untreated rats, in virus-induced mammary tumors from mice, and in a variety of mammary gland lesions from humans. Tenascin was detectable in the stroma of the malignant but not of the benign tumors from all species. An inhibition ELISA, testing homogenates of rat tumors, confirmed that tenascin was present in malignant but not in benign tumors. Thus, tenascin was consistently found to be a stromal marker for epithelial malignancy in the mammary gland. It is concluded that tenascin may be involved in the interactions between the epithelial and mesenchyme-derived (stromal) components of the mammary gland, which are known to influence epithelial carcinogenesis in this organ.

Adenocarcinoma↗
PubMed1975

Intracellular synthesis of mouse mammary tumor virus polypeptides: indication of a precursor glycoprotein.

Mouse mammary tumor virus polypeptides were detected in the cytoplasm of mouse mammary tumor cell cultures using immunological precipitation techniques. The anti-mouse mammary tumor virus serum precipitated the major virion glycoproteins gp49 and gp37.5/33.5 and a viral-related nonvirion glycoprotein of 76,000 daltons. Subcellular fractionation studies revelaed that the cell-associated virion glycoproteins were present in the membrane fraction. Pulsechase experiments indicated that a viral-related nonvirion glycoprotein of 76,000 daltons may be a precursor to one or more of the virion glycoproteins.

Adenocarcinoma↗