Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease.
PDF (1.3M)
Journal: 1992/December - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
PUBMED: 1359541
Abstract:
Overexpression and amplification of the neu (c-erbB2, ERBB2) protooncogene have been implicated in the development of aggressive human breast cancer. To directly assess the effect of mammary gland-specific expression of the neu protooncogene, transgenic mice carrying unactivated neu under the transcriptional control of the mouse mammary tumor virus promoter/enhancer were established. By contrast to the rapid tumor progression observed in several transgenic strains carrying the activated neu transgene, expression of unactivated neu in the mammary epithelium resulted in the development of focal mammary tumors after long latency. The majority of the mammary tumors analyzed expressed elevated levels of neu-encoded mRNA and protein. Overexpression of neu in the mammary tumors was also associated with elevated neu intrinsic tyrosine kinase activity and the de novo tyrosine phosphorylation of several cellular proteins. Interestingly, many of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. These observations suggest that overexpression of the unactivated neu protein can induce metastatic disease after long latency.
Open in
PUBMED | PMC | Google Scholar | Wikipedia
Relations:
Content
Citations
(392)
References
(29)
Diseases
(1)
Conditions
(1)
Drugs
(1)
Chemicals
(2)
Genes
(1)
Organisms
(3)
Processes
(2)
Anatomy
(2)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Proc Natl Acad Sci U S A 89(22): 10578-10582
PMID: 1359541

Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease.

Abstract

Overexpression and amplification of the neu (c-erbB2, ERBB2) protooncogene have been implicated in the development of aggressive human breast cancer. To directly assess the effect of mammary gland-specific expression of the neu protooncogene, transgenic mice carrying unactivated neu under the transcriptional control of the mouse mammary tumor virus promoter/enhancer were established. By contrast to the rapid tumor progression observed in several transgenic strains carrying the activated neu transgene, expression of unactivated neu in the mammary epithelium resulted in the development of focal mammary tumors after long latency. The majority of the mammary tumors analyzed expressed elevated levels of neu-encoded mRNA and protein. Overexpression of neu in the mammary tumors was also associated with elevated neu intrinsic tyrosine kinase activity and the de novo tyrosine phosphorylation of several cellular proteins. Interestingly, many of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. These observations suggest that overexpression of the unactivated neu protein can induce metastatic disease after long latency.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
icon of scanned page 10578
10578
icon of scanned page 10579
10579
icon of scanned page 10580
10580
icon of scanned page 10581
10581
icon of scanned page 10582
10582

Images in this article

Image
Image
on p.10580
Image
Image
on p.10581
Image
Image
on p.10581
Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985 Sep 6;229(4717):974–976. [PubMed] [Google Scholar]
  • Semba K, Kamata N, Toyoshima K, Yamamoto T. A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6497–6501.[PMC free article] [PubMed] [Google Scholar]
  • Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985 Dec 6;230(4730):1132–1139. [PubMed] [Google Scholar]
  • Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986 Jan 16;319(6050):226–230. [PubMed] [Google Scholar]
  • Bargmann CI, Hung MC, Weinberg RA. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell. 1986 Jun 6;45(5):649–657. [PubMed] [Google Scholar]
  • Bargmann CI, Weinberg RA. Oncogenic activation of the neu-encoded receptor protein by point mutation and deletion. EMBO J. 1988 Jul;7(7):2043–2052.[PMC free article] [PubMed] [Google Scholar]
  • Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987 Jul 10;237(4811):178–182. [PubMed] [Google Scholar]
  • Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7159–7163.[PMC free article] [PubMed] [Google Scholar]
  • Di Marco E, Pierce JH, Knicley CL, Di Fiore PP. Transformation of NIH 3T3 cells by overexpression of the normal coding sequence of the rat neu gene. Mol Cell Biol. 1990 Jun;10(6):3247–3252.[PMC free article] [PubMed] [Google Scholar]
  • Yokota J, Yamamoto T, Toyoshima K, Terada M, Sugimura T, Battifora H, Cline MJ. Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo. Lancet. 1986 Apr 5;1(8484):765–767. [PubMed] [Google Scholar]
  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177–182. [PubMed] [Google Scholar]
  • van de Vijver M, van de Bersselaar R, Devilee P, Cornelisse C, Peterse J, Nusse R. Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Mol Cell Biol. 1987 May;7(5):2019–2023.[PMC free article] [PubMed] [Google Scholar]
  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. [PubMed] [Google Scholar]
  • Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 1988 Jul 1;54(1):105–115. [PubMed] [Google Scholar]
  • Bouchard L, Lamarre L, Tremblay PJ, Jolicoeur P. Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell. 1989 Jun 16;57(6):931–936. [PubMed] [Google Scholar]
  • Bargmann CI, Weinberg RA. Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5394–5398.[PMC free article] [PubMed] [Google Scholar]
  • Lemoine NR, Staddon S, Dickson C, Barnes DM, Gullick WJ. Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer. Oncogene. 1990 Feb;5(2):237–239. [PubMed] [Google Scholar]
  • Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987 May 22;49(4):465–475. [PubMed] [Google Scholar]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed] [Google Scholar]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed] [Google Scholar]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed] [Google Scholar]
  • Melton DA, Krieg PA, Rebagliati MR, Maniatis T, Zinn K, Green MR. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056.[PMC free article] [PubMed] [Google Scholar]
  • Kanner SB, Reynolds AB, Parsons JT. Tyrosine phosphorylation of a 120-kilodalton pp60src substrate upon epidermal growth factor and platelet-derived growth factor receptor stimulation and in polyomavirus middle-T-antigen-transformed cells. Mol Cell Biol. 1991 Feb;11(2):713–720.[PMC free article] [PubMed] [Google Scholar]
  • Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell. 1985 Jul;41(3):697–706. [PubMed] [Google Scholar]
  • Cardiff RD, Sinn E, Muller W, Leder P. Transgenic oncogene mice. Tumor phenotype predicts genotype. Am J Pathol. 1991 Sep;139(3):495–501.[PMC free article] [PubMed] [Google Scholar]
  • Guy CT, Cardiff RD, Muller WJ. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992 Mar;12(3):954–961.[PMC free article] [PubMed] [Google Scholar]
  • Kraus MH, Popescu NC, Amsbaugh SC, King CR. Overexpression of the EGF receptor-related proto-oncogene erbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J. 1987 Mar;6(3):605–610.[PMC free article] [PubMed] [Google Scholar]
  • Paterson MC, Dietrich KD, Danyluk J, Paterson AH, Lees AW, Jamil N, Hanson J, Jenkins H, Krause BE, McBlain WA, et al. Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer. Cancer Res. 1991 Jan 15;51(2):556–567. [PubMed] [Google Scholar]
  • Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL, Altman DG. c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer. 1991 Mar;63(3):434–438.[PMC free article] [PubMed] [Google Scholar]
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Copyright notice
Abstract
Overexpression and amplification of the neu (c-erbB2, ERBB2) protooncogene have been implicated in the development of aggressive human breast cancer. To directly assess the effect of mammary gland-specific expression of the neu protooncogene, transgenic mice carrying unactivated neu under the transcriptional control of the mouse mammary tumor virus promoter/enhancer were established. By contrast to the rapid tumor progression observed in several transgenic strains carrying the activated neu transgene, expression of unactivated neu in the mammary epithelium resulted in the development of focal mammary tumors after long latency. The majority of the mammary tumors analyzed expressed elevated levels of neu-encoded mRNA and protein. Overexpression of neu in the mammary tumors was also associated with elevated neu intrinsic tyrosine kinase activity and the de novo tyrosine phosphorylation of several cellular proteins. Interestingly, many of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. These observations suggest that overexpression of the unactivated neu protein can induce metastatic disease after long latency.
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.