Tumorigenesis by mouse mammary tumor virus: Proviral activation of a cellular gene in the common integration region int-2

Dickson, Clive; Smith, Rosalind; Brookes, Sharon; Peters, Gordon

doi:10.1016/0092-8674(84)90383-0

Cited by 333 publications

(178 citation statements)

References 31 publications

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“…Target host cellular genes and the mechanisms by which MMTV activates/inactivates them Early in the 1980s, Nusse and Varmus (1982) and independently, Dickson et al (1984) developed a strategy based on the clonal nature of the MMTV-induced mammary tumors for identifying genes activated by the integration of a MMTV provirus using the viral genome as a`molecular tag' (Varmus, 1982). Their studies focused on inbred mouse strains having a high incidence of MMTV-induced mammary tumors.…”

Section: The Mmtv Infectious Pathwaymentioning

confidence: 99%

“…Using MMTV as a`molecular tag' (Varmus, 1982), members of four cellular gene families have been shown to be rearranged by MMTV integration. These include members of the Wnt (Lee et al, 1995;Nusse and Varmus, 1982;Roelink et al, 1990), Fgf (Dickson et al, 1984;MacArthur et al, 1995;Peters et al, 1989), Notch gene families (Dievart et al, 1999;Callahan, 1987a, Robbins et al, 1992;Sarkar et al, 1994) and the gene encoding the p48 component of eucaryotic translation initiation factor-3 (elF-3p48) (Marchetti et al, 1995); Asano, 1997 [#35].…”

Section: The Mmtv Infectious Pathwaymentioning

confidence: 99%

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MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

2000

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The study of the mouse mammary tumor virus (MMTV) has provided important insights into the mechanisms of gene transcription regulation by steroid hormones, the mode of action of heritable super antigens and the progressive nature of neoplastic transformation in the mammary gland. Here we describe the current situation with respect to the latter aspect of MMTV biology and the prospects for further advance in our understanding of breast cancer in humans that may be expected from a continued study of MMTV-induced mammary neoplasia. MMTV is a heritable somatic mutagen whose target range is limited. Commonly, the tumorigenic capacity of MMTV is restricted to mammary gland, whereas infection is found in a variety of cell types. In order to replicate, proviral DNA must be inserted into the cell DNA and cell division is required to ®x the mutation. Yet only in the mammary epithelium does this lead to neoplastic transformation. This suggests a unique relationship between MMTV and mammary epithelium. In evaluating this relationship, we and others have discovered genes and potential gene pathways that are pertinent in mammary di erentiation and neoplasia. In addition, the clonal nature of these progressive events from normal to malignant phenotype has become increasingly clear. The weight of these observations compel us to conclude that mammary neoplasms arise from multipotent mammary epithelial cells through a process of acquired mutations that are re¯ected in the increasingly malignant nature of the population of progeny produced by these damaged stem cells.

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Section: The Mmtv Infectious Pathwaymentioning

confidence: 99%

Section: The Mmtv Infectious Pathwaymentioning

confidence: 99%

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

2000

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“…Insertional activation of Wnt-1 occurs in approximately 70% of C3H mice that are chronically infected with MMTV (Nusse and Varmus, 1982). Other candidate protooncogenes that are sometimes activated by MMTV proviral insertions include two additional members of the Wnt family, Wnt-3 (Roelink et al, 1990) and Wnt-10b (Lee et al, 1995); three members of the ®broblast growth factor family, Fgf-3/int-2 (Dickson et al, 1984), Fgf-4/hst (Peters et al, 1989), and Fgf-8/AIGF (MacArthur et al, 1995); Notch-4/int-3 (Lee et al, 1995); and int-6 (Asano et al, 1997), encoding a subunit of the translation initiation factor eIF3. Some of these genes, such as Fgf-3 and Wnt-10b, have been validated as oncogenes by transgenic expression (Kwan et al, 1992;Lane and Leder, 1997;Muller et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

2000

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Wnt-1 was ®rst identi®ed as a protooncogene activated by viral insertion in mouse mammary tumors. Transgenic expression of this gene using a mouse mammary tumor virus LTR enhancer causes extensive ductal hyperplasia early in life and mammary adenocarcinomas in approximately 50% of the female transgenic (TG) mice by 6 months of age. Metastasis to the lung and proximal lymph nodes is rare at the time tumors are detected but frequent after the removal of the primary neoplasm. The potent mitogenic e ect mediated by Wnt-1 expression does not require estrogen stimulation; tumors form after an increased latency in estrogen receptor a-null mice. Several genetic lesions, including inactivation of p53 and over-expression of Fgf-3, collaborate with Wnt-1 in leading to mammary tumors, but loss of Sky and inactivation of one allele of Rb do not a ect the rate of tumor formation in Wnt-1 TG mice.

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“…The int-2 gene (fgf-3) was discovered because it is a main target for mouse mammary tumor virus (MMTV) insertional activation in mouse mammary tumoral cells (Peters et al, 1983;Dickson et al, 1984). The hst gene (fgf-4), ®rst identi®ed as a dominant oncogene (Delli Bovi et al, 1987), was found to be also activated in mouse mammary tumors (Peters et al, 1989) albeit at a much lower frequency than fgf-3.…”

Section: Introductionmentioning

confidence: 99%

FGF-3 and FGF-4 elicit distinct oncogenic properties in mouse mammary myoepithelial cells

et al. 1998

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Fibroblast Growth Factors 3 (FGF-3) and 4 (FGF-4) were compared for the e ects they each exert on EF43 mouse cells. This non-transformed mammary cell line appears to be myoepithelial mainly because it expresses a-smooth muscle actin. The EF43 cells were infected with similar vectors that carry either the short fgf-3 sequence (the product of which goes into the secretory pathway), fgf-4 or the selection gene only as control. In syngeneic animals, EF43.fgf-3 cells were tumorigenic only when orthotopically implanted whereas EF43.fgf-4 cells invariably gave rise to aggressive tumors. However, both tumor types were metastatic as evidenced by the blue micrometastases observed when the implanted cells expressed lacZ. In vitro, the FGF-3 producing cells were strongly invasive in matrigel coated chambers whereas the EF43.fgf-4 cells only were invasive in type I-collagen gels. Interestingly, FGF-3 production greatly stimulated the synthesis of pro-MMP-9 (Matrix Metalloprotease-9) and, to a lesser extent, that of pro-MMP-2. FGF-3 also up-regulated the production of plasminogen activators. In contrast, FGF-4 had no e ect on these secretions and the medium conditioned by the EF43.fgf-4 cells displayed the largest plasminogen activator ± inhibitor activity. These results show that FGF-3 and FGF-4 have distinct mechanisms of action on myoepithelial cells.

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Tumorigenesis by mouse mammary tumor virus: Proviral activation of a cellular gene in the common integration region int-2

Cited by 333 publications

References 31 publications

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

FGF-3 and FGF-4 elicit distinct oncogenic properties in mouse mammary myoepithelial cells

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