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. 1987 Apr;61(4):1073–1078. doi: 10.1128/jvi.61.4.1073-1078.1987

Activation of int-1 and int-2 mammary oncogenes in hormone-dependent and -independent mammary tumors of GR mice.

J Mester, E Wagenaar, M Sluyser, R Nusse
PMCID: PMC254065  PMID: 3029401

Abstract

Mammary tumors in the GR mouse strain are caused by the expression of an endogenous provirus of the mouse mammary tumor virus (MMTV). The tumors progress from a hormone-dependent growth phase to autonomous, hormone-independent growth. We studied proviral insertion of MMTV at the int-1 and int-2 mammary oncogenes and the transcription of these genes during progression of a series of transplanted mammary tumors. During the hormone-dependent phase, 6 of 15 transplanted tumors were positive for proviral insertion at int-1 or int-2 or both. These tumors were oligoclonal with respect to the fraction of tumor cells with novel int-1 and int-2 restriction fragments and, apparently, consisted of different tumor cells with proviruses integrated at different oncogenes, including genes that are not yet known. In 10 tumors we detected expression of the int genes, indicating that most tumors contain minor populations of cells with int-1 or int-2 activations. On transplantation the tumors remained oligoclonal during the hormone-dependent phase. The hormone-independent variants of the tumors emerged as clonal outgrowths of cells with MMTV proviruses that could be traced back in the hormone-dependent tumors, but not always those of cells that were positive for insertions near int-1 or int-2. The maintenance of oligoclonality during the hormone-dependent phase suggests a growth-controlling effect of different populations of cells on each other. The clonal, hormone-independent tumors that arise later seem to be the result of mutations that are unrelated to int activation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bentvelzen P., Daams J. H., Hageman P., Calafat J. Genetic transmission of viruses that incite mammary tumor in mice. Proc Natl Acad Sci U S A. 1970 Sep;67(1):377–384. doi: 10.1073/pnas.67.1.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brown A. M., Wildin R. S., Prendergast T. J., Varmus H. E. A retrovirus vector expressing the putative mammary oncogene int-1 causes partial transformation of a mammary epithelial cell line. Cell. 1986 Sep 26;46(7):1001–1009. doi: 10.1016/0092-8674(86)90699-9. [DOI] [PubMed] [Google Scholar]
  3. Cohen J. C., Shank P. R., Morris V. L., Cardiff R., Varmus H. E. Integration of the DNA of mouse mammary tumor virus in virus-infected normal and neoplastic tissue of the mouse. Cell. 1979 Feb;16(2):333–345. doi: 10.1016/0092-8674(79)90010-2. [DOI] [PubMed] [Google Scholar]
  4. Cohen J. C., Varmus H. E. Proviruses of mouse mammary tumor virus in normal and neoplastic tissues from GR and C3Hf mouse strains. J Virol. 1980 Aug;35(2):298–305. doi: 10.1128/jvi.35.2.298-305.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cuypers H. T., Selten G. C., Zijlstra M., de Goede R. E., Melief C. J., Berns A. J. Tumor progression in murine leukemia virus-induced T-cell lymphomas: monitoring clonal selections with viral and cellular probes. J Virol. 1986 Oct;60(1):230–241. doi: 10.1128/jvi.60.1.230-241.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dickson C., Smith R., Brookes S., Peters G. Tumorigenesis by mouse mammary tumor virus: proviral activation of a cellular gene in the common integration region int-2. Cell. 1984 Jun;37(2):529–536. doi: 10.1016/0092-8674(84)90383-0. [DOI] [PubMed] [Google Scholar]
  7. Gallahan D., Callahan R. Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors. J Virol. 1987 Jan;61(1):66–74. doi: 10.1128/jvi.61.1.66-74.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hilgers J., Bentvelzen P. Interaction between viral and genetic factors in murine mammary cancer. Adv Cancer Res. 1978;26:143–195. doi: 10.1016/s0065-230x(08)60087-1. [DOI] [PubMed] [Google Scholar]
  9. Kasid A., Lippman M. E., Papageorge A. G., Lowy D. R., Gelmann E. P. Transfection of v-rasH DNA into MCF-7 human breast cancer cells bypasses dependence on estrogen for tumorigenicity. Science. 1985 May 10;228(4700):725–728. doi: 10.1126/science.4039465. [DOI] [PubMed] [Google Scholar]
  10. Macinnes J. I., Chan E. C., Percy D. H., Morris V. L. Mammary tumors from GR mice contain more than one population of mouse mammary tumor virus-infected cells. Virology. 1981 Aug;113(1):119–129. doi: 10.1016/0042-6822(81)90141-0. [DOI] [PubMed] [Google Scholar]
  11. Michalides R., Wagenaar E., Groner B., Hynes N. E. Mammary tumor virus proviral DNA in normal murine tissue and non-virally induced mammary tumors. J Virol. 1981 Aug;39(2):367–376. doi: 10.1128/jvi.39.2.367-376.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Michalides R., Wagenaar E., Sluyser M. Mammary tumor virus DNA as a marker for genotypic variance within hormone-responsive GR mouse mammary tumors. Cancer Res. 1982 Mar;42(3):1154–1158. [PubMed] [Google Scholar]
  13. Michalides R., van Nie R., Nusse R., Hynes N. E., Groner B. Mammary tumor induction loci in GR and DBAf mice contain one provirus of the mouse mammary tumor virus. Cell. 1981 Jan;23(1):165–173. doi: 10.1016/0092-8674(81)90281-6. [DOI] [PubMed] [Google Scholar]
  14. Moore R., Casey G., Brookes S., Dixon M., Peters G., Dickson C. Sequence, topography and protein coding potential of mouse int-2: a putative oncogene activated by mouse mammary tumour virus. EMBO J. 1986 May;5(5):919–924. doi: 10.1002/j.1460-2075.1986.tb04304.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nusse R., Varmus H. E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982 Nov;31(1):99–109. doi: 10.1016/0092-8674(82)90409-3. [DOI] [PubMed] [Google Scholar]
  16. Nusse R., de Moes J., Hilkens J., van Nie R. Localization of a gene for expression of mouse mammary tumor virus antigens in the GR/Mtv-2- mouse strain. J Exp Med. 1980 Sep 1;152(3):712–719. doi: 10.1084/jem.152.3.712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nusse R., van Ooyen A., Cox D., Fung Y. K., Varmus H. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature. 1984 Jan 12;307(5947):131–136. doi: 10.1038/307131a0. [DOI] [PubMed] [Google Scholar]
  18. O'Donnell P. V., Fleissner E., Lonial H., Koehne C. F., Reicin A. Early clonality and high-frequency proviral integration into the c-myc locus in AKR leukemias. J Virol. 1985 Aug;55(2):500–503. doi: 10.1128/jvi.55.2.500-503.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Percy D. H., Morris V. L., MacInnes J. I. Comparison of biologic behavior and histology of transplanted mammary tumors in GR mice. J Natl Cancer Inst. 1982 Oct;69(4):933–938. [PubMed] [Google Scholar]
  20. Peters G., Brookes S., Smith R., Dickson C. Tumorigenesis by mouse mammary tumor virus: evidence for a common region for provirus integration in mammary tumors. Cell. 1983 Jun;33(2):369–377. doi: 10.1016/0092-8674(83)90418-x. [DOI] [PubMed] [Google Scholar]
  21. Peters G., Lee A. E., Dickson C. Activation of cellular gene by mouse mammary tumour virus may occur early in mammary tumour development. Nature. 1984 May 17;309(5965):273–275. doi: 10.1038/309273a0. [DOI] [PubMed] [Google Scholar]
  22. Peters G., Lee A. E., Dickson C. Concerted activation of two potential proto-oncogenes in carcinomas induced by mouse mammary tumour virus. Nature. 1986 Apr 17;320(6063):628–631. doi: 10.1038/320628a0. [DOI] [PubMed] [Google Scholar]
  23. Sluyser M., Evers S. G., De Goeij C. C. Sex hormone receptors in mammary tumours of GR mice. Nature. 1976 Sep 30;263(5576):386–389. doi: 10.1038/263386a0. [DOI] [PubMed] [Google Scholar]
  24. Sluyser M., Van Nie R. Estrogen receptor content and hormone-responsive growth of mouse mammary tumors. Cancer Res. 1974 Dec;34(12):3253–3257. [PubMed] [Google Scholar]
  25. Van Nie R., Verstraeten A. A., De Moes J. Genetic transmission of mammary tumour virus by GR mice. Int J Cancer. 1977 Mar 15;19(3):383–390. doi: 10.1002/ijc.2910190316. [DOI] [PubMed] [Google Scholar]
  26. van Nie R., de Moes J. Development of a congeneic line of the GR mouse strain without early mammary tumours. Int J Cancer. 1977 Oct 15;20(4):588–594. doi: 10.1002/ijc.2910200417. [DOI] [PubMed] [Google Scholar]
  27. van Ooyen A., Nusse R. Structure and nucleotide sequence of the putative mammary oncogene int-1; proviral insertions leave the protein-encoding domain intact. Cell. 1984 Nov;39(1):233–240. doi: 10.1016/0092-8674(84)90209-5. [DOI] [PubMed] [Google Scholar]

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