Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. Mar 1992; 12(3): 954–961.
PMCID: PMC369527

Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease.

Abstract

The effect of mammary gland-specific expression of the polyomavirus middle T antigen was examined by establishing lines of transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/enhancer. By contrast to most transgenic strains carrying activated oncogenes, expression of polyomavirus middle T antigen resulted in the widespread transformation of the mammary epithelium and the rapid production of multifocal mammary adenocarcinomas. Interestingly, the majority of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. Taken together, these results suggest that middle T antigen acts as a potent oncogene in the mammary epithelium and that cells that express it possess an enhanced metastatic potential.

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 (2.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

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.
  • Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD, Brinster RL. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. [PubMed]
  • Aguzzi A, Wagner EF, Williams RL, Courtneidge SA. Sympathetic hyperplasia and neuroblastomas in transgenic mice expressing polyoma middle T antigen. New Biol. 1990 Jun;2(6):533–543. [PubMed]
  • Bautch VL, Toda S, Hassell JA, Hanahan D. Endothelial cell tumors develop in transgenic mice carrying polyoma virus middle T oncogene. Cell. 1987 Nov 20;51(4):529–537. [PubMed]
  • Berebbi M, Martin PM, Berthois Y, Bernard AM, Blangy D. Estradiol dependence of the specific mammary tissue targeting of polyoma virus oncogenicity in nude mice. Oncogene. 1990 Apr;5(4):505–509. [PubMed]
  • Bolen JB, Thiele CJ, Israel MA, Yonemoto W, Lipsich LA, Brugge JS. Enhancement of cellular src gene product associated tyrosyl kinase activity following polyoma virus infection and transformation. Cell. 1984 Oct;38(3):767–777. [PubMed]
  • Brinster RL, Chen HY, Messing A, van Dyke T, Levine AJ, Palmiter RD. Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumors. Cell. 1984 Jun;37(2):367–379. [PubMed]
  • Cheng SH, Harvey R, Espino PC, Semba K, Yamamoto T, Toyoshima K, Smith AE. Peptide antibodies to the human c-fyn gene product demonstrate pp59c-fyn is capable of complex formation with the middle-T antigen of polyomavirus. EMBO J. 1988 Dec 1;7(12):3845–3855. [PMC free article] [PubMed]
  • 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]
  • Cook DN, Hassell JA. The amino terminus of polyomavirus middle T antigen is required for transformation. J Virol. 1990 May;64(5):1879–1887. [PMC free article] [PubMed]
  • Courtneidge SA, Heber A. An 81 kd protein complexed with middle T antigen and pp60c-src: a possible phosphatidylinositol kinase. Cell. 1987 Sep 25;50(7):1031–1037. [PubMed]
  • Courtneidge SA, Smith AE. Polyoma virus transforming protein associates with the product of the c-src cellular gene. Nature. 1983 Jun 2;303(5916):435–439. [PubMed]
  • Dawe CJ, Freund R, Mandel G, Ballmer-Hofer K, Talmage DA, Benjamin TL. Variations in polyoma virus genotype in relation to tumor induction in mice. Characterization of wild type strains with widely differing tumor profiles. Am J Pathol. 1987 May;127(2):243–261. [PMC free article] [PubMed]
  • 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]
  • Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991 Apr 5;65(1):13–24. [PubMed]
  • Huang AL, Ostrowski MC, Berard D, Hager GL. Glucocorticoid regulation of the Ha-MuSV p21 gene conferred by sequences from mouse mammary tumor virus. Cell. 1981 Dec;27(2 Pt 1):245–255. [PubMed]
  • Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249–270. [PubMed]
  • Israel MA, Chan HW, Hourihan SL, Rowe WP, Martin MA. Biological activity of polyoma viral DNA in mice and hamsters. J Virol. 1979 Mar;29(3):990–996. [PMC free article] [PubMed]
  • Kornbluth S, Sudol M, Hanafusa H. Association of the polyomavirus middle-T antigen with c-yes protein. Nature. 1987 Jan 8;325(7000):171–173. [PubMed]
  • Kypta RM, Hemming A, Courtneidge SA. Identification and characterization of p59fyn (a src-like protein tyrosine kinase) in normal and polyoma virus transformed cells. EMBO J. 1988 Dec 1;7(12):3837–3844. [PMC free article] [PubMed]
  • Leone A, Flatow U, King CR, Sandeen MA, Margulies IM, Liotta LA, Steeg PS. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell. 1991 Apr 5;65(1):25–35. [PubMed]
  • Lidereau R, Callahan R, Dickson C, Peters G, Escot C, Ali IU. Amplification of the int-2 gene in primary human breast tumors. Oncogene Res. 1988 Feb;2(3):285–291. [PubMed]
  • Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. [PubMed]
  • 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]
  • Mes AM, Hassell JA. Polyoma viral middle T-antigen is required for transformation. J Virol. 1982 May;42(2):621–629. [PMC free article] [PubMed]
  • Montesano R, Pepper MS, Möhle-Steinlein U, Risau W, Wagner EF, Orci L. Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell. 1990 Aug 10;62(3):435–445. [PubMed]
  • 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]
  • Pallas DC, Shahrik LK, Martin BL, Jaspers S, Miller TB, Brautigan DL, Roberts TM. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell. 1990 Jan 12;60(1):167–176. [PubMed]
  • Pattengale PK, Stewart TA, Leder A, Sinn E, Muller W, Tepler I, Schmidt E, Leder P. Animal models of human disease. Pathology and molecular biology of spontaneous neoplasms occurring in transgenic mice carrying and expressing activated cellular oncogenes. Am J Pathol. 1989 Jul;135(1):39–61. [PMC free article] [PubMed]
  • Quaife CJ, Pinkert CA, Ornitz DM, Palmiter RD, Brinster RL. Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell. 1987 Mar 27;48(6):1023–1034. [PubMed]
  • Quinn P, Barros C, Whittingham DG. Preservation of hamster oocytes to assay the fertilizing capacity of human spermatozoa. J Reprod Fertil. 1982 Sep;66(1):161–168. [PubMed]
  • Rassoulzadegan M, Courtneidge SA, Loubière R, el Baze P, Cuzin F. A variety of tumours induced by the middle T antigen of polyoma virus in a transgenic mouse family. Oncogene. 1990 Oct;5(10):1507–1510. [PubMed]
  • Rüther U, Garber C, Komitowski D, Müller R, Wagner EF. Deregulated c-fos expression interferes with normal bone development in transgenic mice. Nature. 325(6103):412–416. [PubMed]
  • Seed B, Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc Natl Acad Sci U S A. 1987 May;84(10):3365–3369. [PMC free article] [PubMed]
  • 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]
  • 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]
  • Soeda E, Arrand JR, Smolar N, Walsh JE, Griffin BE. Coding potential and regulatory signals of the polyoma virus genome. Nature. 1980 Jan 31;283(5746):445–453. [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Talmage DA, Freund R, Young AT, Dahl J, Dawe CJ, Benjamin TL. Phosphorylation of middle T by pp60c-src: a switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis. Cell. 1989 Oct 6;59(1):55–65. [PubMed]
  • Treisman R, Novak U, Favaloro J, Kamen R. Transformation of rat cells by an altered polyoma virus genome expressing only the middle-T protein. Nature. 1981 Aug 13;292(5824):595–600. [PubMed]
  • Walter G, Ruediger R, Slaughter C, Mumby M. Association of protein phosphatase 2A with polyoma virus medium tumor antigen. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2521–2525. [PMC free article] [PubMed]
  • Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature. 1985 May 16;315(6016):239–242. [PubMed]
  • Williams RL, Courtneidge SA, Wagner EF. Embryonic lethalities and endothelial tumors in chimeric mice expressing polyoma virus middle T oncogene. Cell. 1988 Jan 15;52(1):121–131. [PubMed]
  • Williams RL, Risau W, Zerwes HG, Drexler H, Aguzzi A, Wagner EF. Endothelioma cells expressing the polyoma middle T oncogene induce hemangiomas by host cell recruitment. Cell. 1989 Jun 16;57(6):1053–1063. [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...