Abstract
The MMTV/neu transgenic (Tg) mice spontaneously develop mammary tumors stochastically after a long latent period, suggesting that the c-neu/erbB2 oncogene is not sufficient for tumor formation. To identify putative collaborator(s) of the c-neu/erbB2, we used the provirus insertional mutagenesis approach with mammary tumors arising in MMTV/neu Tg mice infected with the mouse mammary tumor virus (MMTV). The Notch1 gene was identified as a novel target for MMTV provirus insertional activation. In Notch1-rearranged tumors, the Notch1 gene was interrupted by the MMTV provirus insertion upstream of the exons coding for the TM domain. These insertions led to overexpression of novel 5′ truncated ∼7 kb RNA coding for 280 kDa mutant protein harboring only the Notch1 ectodomain, N(EC)mut. These may be involved in tumor formation. Another consequence of these insertions was the expression of truncated 3′ Notch1 transcripts (3.5 – 4.5 kb) and proteins (86 – 110 kDa) deleted of most of the extracellular sequences (Notch1intra). We found that 3′ truncated Notch1intra can transform HC11 mouse mammary epithelial cells in vitro. Deletion analysis revealed that the ankyrin-repeats and the domain 1 (aa 1751 – 1821) are required, while a signal peptide, the two conserved cysteines (C1652 and C1685) and the OPA and PEST sequences are dispensable for transformation. These results indicate that the N-terminally truncated Notch1intra protein behaves as an oncogene in this system.
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Acknowledgements
This work was supported by grants to P Jolicoeur from the Medical Research Council of Canada and from the Canadian Breast Cancer Research initiative through the National Cancer Institute of Canada. We are grateful to J Rossant and H Weintraub for providing Notch1 cDNA clones, to H Varmus for int-1 and MMTV plasmids, to G Shackleford for int-2/C3L, wnt-3 pBG14 and pCG1 probes and to G Peters for int-2/U779 and hst/HHI probes. We thank C Hoemann for her critical reading of the manuscript. We thank B Laganière and G Massé for their excellent technical assistance, and M Diévart for her help in the construction of the Notch1 mutants.
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Diévart, A., Beaulieu, N. & Jolicoeur, P. Involvement of Notch1 in the development of mouse mammary tumors. Oncogene 18, 5973–5981 (1999). https://doi.org/10.1038/sj.onc.1202991
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DOI: https://doi.org/10.1038/sj.onc.1202991
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