TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas

Jhappan, Chamelli; Stahle, Cheryl; Harkins, Richard N.; Fausto, Nelson; Smith, Gilbert H.; Merlino, Glenn

doi:10.1016/0092-8674(90)90076-q

Cited by 654 publications

(385 citation statements)

References 33 publications

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“…We report here inducible liver pathologies in transgenic mice expressing the PMLRARa protein driven by the mouse MT promoter. This promoter had been previously shown to e ciently direct transgene expression in a wide variety of murine tissues as well as to be inducible by heavy metals (Heisterkamp et al, 1990;Palmiter et al, 1983Palmiter et al, , 1985Crenshaw et al, 1987;Jhappan et al, 1990;Sandgren et al, 1990). Nine of the 10 founder mice lines resulting from MT-PMLRARa transgene injection were considered as nonexpressors.…”

Section: Discussionmentioning

confidence: 99%

The acute promyelocytic leukemia PML-RARα protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice

et al. 1997

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The PML-RARa hybrid protein generated by the t(15;17) translocation in acute promyelocytic leukemia (APL) is thought to play a central role in the oncogenic process. However, analysis of the oncogenic activity of the fusion protein in tissue culture assays or in mice has been hampered by its apparent toxicity in multiple murine cells. To circumvent this problem, we generated an inducible line of transgenic mice, MT135, in which the expression of PML-RARa is driven by the metallothionein promoter. After 5 days zinc stimulation, 27 out of 54 mice developed hepatic preneoplasia and neoplasia including foci of basophilic hepatocytes, dysplasia and carcinoma with a signi®cantly higher incidence of lesions in females than in males. The rapid onset of liver pathologies was dependent on overexpression of the transgene since it was not detected in noninduced transgenic animals of the same age. The PML-RARa protein was always present in altered tissues at much higher levels than in the surrounding normal liver tissues. In addition, overexpression of PMLRARa resulted in a strong proliferative response in the hepatocytes. We conclude that overexpression of PMLRARa deregulates cell proliferation and can induce tumorigenic changes in vivo.

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Section: Discussionmentioning

confidence: 99%

The acute promyelocytic leukemia PML-RARα protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice

et al. 1997

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“…TGFa is the most commonly identi®ed EGF-like growth factor in primary breast tumors as evidenced by the presence of TGFa mRNA and/or protein in 30 ± 70% of cases reported (reviewed in Rudland et al, 1995). In addition, overexpression of TGFa in the mammary gland of transgenic mice is potently oncogenic (Sandgren et al, 1990(Sandgren et al, , 1995Jhappan et al, 1990;Matsui et al, 1990;Halter et al, 1992;Smith et al, 1995), and coexpression of TGFa with other oncogenes shortens tumor latency (Sandgren et al, 1995;Amundadottir et al, 1995Amundadottir et al, , 1996Muller et al, 1996;Davies et al, 1999).…”

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

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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.

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“…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%

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

1998

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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.

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TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas

Cited by 654 publications

References 33 publications

The acute promyelocytic leukemia PML-RARα protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice

The acute promyelocytic leukemia PML-RARα protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice

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

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

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