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

Leder, Aya; Pattengale, Paul K.; Kuo, Alfred C.; Stewart, Timothy A.; Leder, Philip

doi:10.1016/0092-8674(86)90280-1

Cited by 402 publications

(199 citation statements)

References 34 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…These transgenes are generally expressed in the mammary epithelium as a result of their fusion with the mouse mammary virus tumor virus (MMTV) promoter/enhancer (Stewart et al, 1984;Leder et al, 1986;Muller et al, 1988;Krane and Leder, 1996). Such lines generate mammary gland tumors, the oncogenic behavior and morphology of which are directly dependent upon the speci®c oncogenic (initiating) transgene carried by the line (Cardi et al, 1991).…”

Section: Resultsmentioning

confidence: 99%

“…Neu, heregulin/NDF, TGFa, v-Ha-ras and c-myc were expressed in the mammary gland from the mouse mammary tumor virus long terminal repeat (MMTV-LTR) promoter/enhancer, the mouse metallothionein promoter (MT) or the zeta globin promoter. The following cell lines were used: 16MB9A, M158, 13Mala and Myc#83 from mammary tumors arising in MMTV-c-myc transgenic mice (line M) (Stewart et al, 1984;Leder et al, 1986;Amundadottir et al, 1996); IJ9921 from a MMTV-heregulin/NDF transgenic mouse tumor (line TG.IJ) (Krane and , TGFa#13 from a MT-TGFa mouse (MT100 line) (Jhappan et al, 1990;Amundadottir et al, 1996); n-Neu from a MMTV-c-neu mouse (nonactivated Neu, line N202) (Guy et al, 1992); NF639, SMF and NAF from MMTV-neu mice (activated Neu; line TG.NF) (Muller et al, 1988); SH1.1 from a MMTV-v-Ha-ras mouse (TG.SH line) and AC236, AC711 and AC816 from zeta globin promoter-v-Ha-ras mice (TG.AC line) (Sinn et al, 1987;Leder et al, 1990). The cells were routinely grown in DMEM supplemented with 10% bovine calf serum (Gibco-BRL, Gaithersburg, MD), 4 mM glutamine (Bio-Whittaker, Walkersville, MD), penicillin (50 U/ml) and streptomycin (50 mg/ml) (Sigma, St Louis, MO).…”

Section: Cell Lines and Tumorsmentioning

confidence: 99%

See 1 more Smart Citation

Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes

1998

Self Cite

View full text Add to dashboard Cite

We have assessed ®ve signal transduction pathways to determine the role each might play in the malignant transformation of mammary epithelium initiated by neu, heregulin/NDF, TGFa, v-Ha-ras and c-myc in transgenic mice. The study involves a molecular and pharmacologic assessment of Erk/MAP kinase, Jnk/SAP kinase, PI 3-kinase, protein kinase C, and the Src-related kinases Lck and Fyn. Our results indicate that oncogenes capable of transforming mammary gland epithelium activate and require speci®c signal transduction pathways. For example, mammary tumors initiated by neu, vHa-ras and c-myc have high levels of active Erk/MAP kinase and their anchorage independent growth is strongly inhibited by PD098059, an inhibitor of Mek/ MAP kinase kinase. By contrast, Erk/MAP kinase activity is weak in tumors initiated by TFGa and heregulin/NDF and the corresponding cell lines are not growth inhibited by PD098059. Similarly, PI 3-kinase is strongly activated in neu, TGFa and heregulin/NDF initiated tumor cell lines, but not in c-myc or v-Ha-ras initiated tumor cell lines. The anchorage independent growth of all these tumor cell lines are, however, inhibited by the speci®c PI 3-kinase inhibitor LY294001. Further illustrating this oncogene-based speci®city, PP1, a speci®c inhibitor of the Src-like kinases, Lck and Fyn, blocks anchorage-independent cell growth only in the TGFa initiated mammary tumor cell line. Taken together with additional observations, we conclude that certain oncogenes reliably require the recruitment/activation of speci®c signal transduction pathways. Such speci®c relationships between the initiating oncogene and a required pathway may re¯ect a direct activating e ect or the parallel activation of a pathway that is a necessary oncogenic collaborator for transformation in the mammary gland. The work points to a molecular basis for targeting therapy when an initiating oncogene can be implicated; for example, because of ampli®cation, increased expression, genetic alteration, or heritable characteristics.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Cell Lines and Tumorsmentioning

confidence: 99%

Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes

1998

Self Cite

View full text Add to dashboard Cite

show abstract

“…Together these results strongly support that the expression of the FUS-CHOP oncogene does not require further complementary genetic changes in order to transform the adipose target cell. The apparent single-step action of the FUS-CHOP contrasts with previous experience with transgenic mice bearing other oncogenes (Adams et al, 1985;Leder et al, 1986;Quaife et al, 1987;Ruther et al, 1987;Sinn et al, 1987). However, if one considers the combined e ects of FUS-CHOP on di erentiation and proliferation controls, it seems reasonable to think that the single chromosome abnormality that leads to the generation of this protein may be all that is needed for the liposarcoma target cells to become transformed.…”

Section: The Role Of Fus-chop In the Genesis Of Liposarcomasmentioning

confidence: 89%

The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice

et al. 2000

View full text Add to dashboard Cite

The characteristic t(12;16)(q13;p11) chromosomal translocation, which leads to gene fusion that encodes the FUS-CHOP chimeric protein, is associated with human liposarcomas. The altered expression of FUS-CHOP has been implicated in a characteristic subgroup of human liposarcomas. We have introduced the FUS-CHOP transgene into the mouse genome in which the expression of the transgene is successfully driven by the elongation factor 1a (EF1a) promoter to all tissues. The consequent overexpression of FUS-CHOP results in most of the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation of intracellular lipid, induction of adipocyte-speci®c genes and a concordant block in the di erentiation program. We have demonstrated that liposarcomas in the FUS-CHOP transgenic mice express high levels of the adipocyte regulatory protein PPARg, whereas it is not expressed in embryonic ®broblasts from these animals following induction to di erentiation toward the adipocyte lineage, indicating that the in vitro system does not really re¯ect the in vivo situation and the developmental defect is downstream of PPARg expression. No tumors of other tissues were found in these transgenic mice despite widespread activity of the EF1a promoter. This establishes FUS-CHOP overexpression as a key determinant of human liposarcomas and provide the ®rst in vivo evidence for a link between a fusion gene created by a chromosomal translocation and a solid tumor.

show abstract

“…Mice that overexpress c-myc in the mammary gland are predisposed to develop mammary neoplasia (Stewart et al, 1984;Leder et al, 1986;Andres et al, 1988;Oncogene (2000) 19, 1092 ± 1096 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc *Correspondence: EP Sandgren Schoenenberger et al, 1988;Sandgren et al, 1995). Furthermore, as for TGFa, co-expression of c-myc with growth factors or other oncogenes increases the incidence of tumors and shortens their latency (Sinn et al, 1987;Andres et al, 1988;Sandgren et al, 1995;Amundadottir et al, 1995Amundadottir et al, , 1996Jager et al, 1997;McCormack et al, 1998).…”

Section: Tgfa and C-myc In Human Breast Cancermentioning

confidence: 99%

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

Rose-Hellekant

Sandgren

2000

Oncogene

View full text Add to dashboard Cite

The growth factor transforming growth factor alpha (TGFa) and the nuclear transcription factor c-myc often are overexpressed by human breast cancer cells. To produce models of breast disease with these etiologies, mice were generated that carried TGF-a-or c-mycencoding transgenes. Transgene targeting employed the whey acidic protein (WAP) gene promoter, which is expressed in pregnant and lactating mammary epithelial cells. Non-virgin WAP-TGFa transgenic mice displayed accelerated mammary development during pregnancy, delayed post-parturient mammary involution, a progressive increase in the number of hyperplastic alveolar nodules (HANs), and development of mammary carcinoma with a mean latency of 9 months. Non-virgin WAP-c-myc transgenic mice displayed accelerated mammary gland development during pregnancy and development of mammary carcinomas with a latency of 8 months. Bitransgenic mice carrying both WAP-TGFa and WAPc-myc displayed a dramatic acceleration of tumor development. These models identify the overexpression of TGFa or c-myc as etiological factors in the development of mammary neoplasia and demonstrate the increased severity of disease when both molecular alterations are present in the same cell.

show abstract

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

Cited by 402 publications

References 34 publications

Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes

Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes

The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

Contact Info

Product

Resources

About