Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene

Muller, William J.; Sinn, Eric; Pattengale, Paul K.; Wallace, Racheal; Leder, Philip

doi:10.1016/0092-8674(88)90184-5

Cited by 1,052 publications

(806 citation statements)

References 40 publications

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“…The ultrastructural features of cells in the tumors were similar to those of poorly di erentiated cells and the light microscopic features of the tumors did not resemble those of human oligodendrogliomas. In contrast to the low frequency of oligodendrocytic tumors in MBP/c-neu transgenic mice, a high frequency of mammary adenocarcinomas was observed in transgenic mice that expressed the neu oncogene in mammary epithelium (Muller et al, 1988;Bouchard et al, 1989).…”

Section: Introductionmentioning

confidence: 68%

Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity

et al. 1998

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Section: Introductionmentioning

confidence: 68%

Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity

et al. 1998

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“…Thus, overexpression of the WT IGF-IR is sufficient for mammary epithelial transformation and possesses a similar capacity to transform mammary epithelium as a constitutively active IGF-IR. The IGF-IR also appears to be as effective or more effective at transforming mammary epithelial cells than erbB2 as overexpression of WT IGF-IR induced palpable tumors by 10-11 weeks of age while overexpression of WT and constitutively active erbB2 resulted in the development of palpable tumors at 29 weeks (Guy et al, 1992) and 13 weeks (Muller et al, 1988), respectively.…”

Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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Overexpression and hyperactivation of the type I insulinlike growth factor receptor (IGF-IR) has been observed in human breast tumor biopsies. In addition, in vitro studies indicate that overexpression of IGF-IR is sufficient to transform cells such as mouse embryo fibroblasts and this receptor promotes proliferation and survival in breast cancer cell lines. To fully understand the function of the IGF-IR in tumor initiation and progression, transgenic mice containing human IGF-IR under a doxycyclineinducible MMTV promoter system were generated. Administration of 2 mg/ml doxycycline in the animals' water supply beginning at 21 days of age resulted in elevated levels of IGF-IR in mammary epithelial cells as detected by Western blotting and immunohistochemistry. Whole mount analysis of 55-day-old mouse mammary glands revealed that IGF-IR overexpression significantly impaired ductal elongation. Moreover, histological analyses revealed multiple hyperplasic lesions in the mammary glands of these 55-day-old mice. The formation of palpable mammary tumors was evident at approximately 2 months of age and was associated with increased levels of IGF-IR signaling molecules including phosphorylated Akt, Erk1/Erk2 and STAT3. Therefore, these transgenic mice provide evidence that IGF-IR overexpression is sufficient to induce mammary epithelial hyperplasia and tumor formation in vivo and provide a model to further understand the function of IGF-IR in mammary epithelial transformation.

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“…Gene amplification and overexpression of Neu/ErbB-2, a member of the epidermal growth factor receptor tyrosine kinase family, is found in 25-30% of primary breast cancer patients, who display a trend of early stage metastasis and poor survival rate (Slamon et al, 1987). These clinical observations have been clearly supported by the establishment of several Neu/ErbB-2-dependent transgenic models of breast cancer, showing a causal relationship between overexpression of Neu/ErbB-2 and the development of metastatic breast tumors (Muller et al, 1988;Siegel et al, 1994;Ursini-Siegel et al, 2007). In addition, it is becoming clear that Neu/ErbB-2-induced signaling pathways can be influenced by other signaling pathways leading to breast tumorigenesis.…”

Section: Introductionmentioning

confidence: 93%

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Northey

Primeau

et al. 2010

Oncogene

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RhoA, Rac1 and Cdc42, the best-characterized members of the Rho family of small GTPases, are critical regulators of many cellular activities. Cdc42 GTPaseactivating protein (CdGAP) is a serine-and proline-rich RhoGAP protein showing GAP activity against both Cdc42 and Rac1 but not RhoA. CdGAP is phosphorylated downstream of the MEK-ERK (extracellular signalregulated kinase) pathway in response to serum and is required for normal cell spreading and polarized lamellipodia formation. In this study, we found that CdGAP protein and mRNA levels are highly increased in mammary tumor explants expressing an activated Neu/ ErbB-2 (Neu-NT) receptor. In response to transforming growth factor-b (TGFb) stimulation, Neu-NT-expressing mammary tumor explants demonstrate a clear induction in cell motility and invasion. We show that downregulation of CdGAP expression by small interfering RNA abrogates the ability of TGFb to induce cell motility and invasion of Neu-NT-expressing mammary tumor explants. However, it has no effect on TGFb-mediated cell adhesion on type 1 collagen and fibronectin. Interestingly, protein expression of E-Cadherin is highly increased in Neu-NT-expressing mammary tumor explants depleted of CdGAP. In addition, complete loss of E-Cadherin expression is not observed in CdGAP-depleted cells during TGFb-mediated epithelial to mesenchymal transition. Downregulation of the CdGAP expression also decreases cell proliferation of Neu-NT-expressing mammary tumor explants independently of TGFb. Rescue analysis using re-expression of various CdGAP deletion-mutant proteins revealed that the proline-rich domain (PRD) but not the GAP domain of CdGAP is essential to mediate TGFbinduced cell motility and invasion. Finally, we found that TGFb induces the expression and phosphorylation of CdGAP in mammary epithelial NMuMG cells. Taken together, these studies identify CdGAP as a novel molecular target in TGFb signaling and implicate CdGAP as an essential component in the synergistic interaction between TGFb and Neu/ErbB-2 signaling pathways in breast cancer cells.

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Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene

Cited by 1,052 publications

References 40 publications

Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity

Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

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