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Mol Cell Biol. Jan 1992; 12(1): 147–154.
PMCID: PMC364078

Transgenes expressing the Wnt-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice.

Abstract

The Wnt-1 and int-2 proto-oncogenes are transcriptionally activated by mouse mammary tumor virus insertion mutations in virus-induced tumors and encode secretory glycoproteins. To determine whether these two genes can cooperate during carcinogenesis, we have crossed two previously characterized lines of transgenic mice to obtain bitransgenic animals carrying both Wnt-1 and int-2 transgenes under the control of the mouse mammary tumor virus long terminal repeat. Mammary carcinomas appear earlier and with higher frequency in the bitransgenic animals, especially the males, than in either parental line. Nearly all bitransgenic males develop mammary neoplasms within 8 months of birth, whereas only 15% of Wnt-1 transgenic males and none of the int-2 transgenic males have tumors. In virgin bitransgenic females, tumors occur approximately 2 months earlier than in their Wnt-1 transgenic siblings; int-2 transgenic females rarely exhibit tumors. Preneoplastic glands from the bitransgenic animals of either sex demonstrate pronounced epithelial hyperplasia similar to that seen in Wnt-1 transgenic virgin females and males, and both transgenes are expressed in the hyperplastic glands and mammary tumors. RNA from the int-2 transgene is more abundant in mammary glands from bitransgenic animals than from int-2 transgenic animals; the increase is associated with high levels of RNA specific for keratin genes 14 and 18, suggesting that Wnt-1-induced epithelial hyperplasia is responsible for the observed increase in expression of the int-2 transgene.

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Selected References

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  • Acland P, Dixon M, Peters G, Dickson C. Subcellular fate of the int-2 oncoprotein is determined by choice of initiation codon. Nature. 1990 Feb 15;343(6259):662–665. [PubMed]
  • Bishop JM. Molecular themes in oncogenesis. Cell. 1991 Jan 25;64(2):235–248. [PubMed]
  • 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]
  • Bradley RS, Brown AM. The proto-oncogene int-1 encodes a secreted protein associated with the extracellular matrix. EMBO J. 1990 May;9(5):1569–1575. [PMC free article] [PubMed]
  • Brown AM, Wildin RS, Prendergast TJ, Varmus HE. 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. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. [PMC free article] [PubMed]
  • Cory S, Adams JM. Transgenic mice and oncogenesis. Annu Rev Immunol. 1988;6:25–48. [PubMed]
  • Dickson C, Peters G. Potential oncogene product related to growth factors. Nature. 326(6116):833–833. [PubMed]
  • 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. [PubMed]
  • Dickson C, Smith R, Brookes S, Peters G. Proviral insertions within the int-2 gene can generate multiple anomalous transcripts but leave the protein-coding domain intact. J Virol. 1990 Feb;64(2):784–793. [PMC free article] [PubMed]
  • Dixon M, Deed R, Acland P, Moore R, Whyte A, Peters G, Dickson C. Detection and characterization of the fibroblast growth factor-related oncoprotein INT-2. Mol Cell Biol. 1989 Nov;9(11):4896–4902. [PMC free article] [PubMed]
  • Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. [PubMed]
  • Fung YK, Shackleford GM, Brown AM, Sanders GS, Varmus HE. Nucleotide sequence and expression in vitro of cDNA derived from mRNA of int-1, a provirally activated mouse mammary oncogene. Mol Cell Biol. 1985 Dec;5(12):3337–3344. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Goldfarb M. The fibroblast growth factor family. Cell Growth Differ. 1990 Sep;1(9):439–445. [PubMed]
  • Goldfarb M, Deed R, MacAllan D, Walther W, Dickson C, Peters G. Cell transformation by Int-2--a member of the fibroblast growth factor family. Oncogene. 1991 Jan;6(1):65–71. [PubMed]
  • Gray DA, Jackson DP, Percy DH, Morris VL. Activation of int-1 and int-2 loci in GRf mammary tumors. Virology. 1986 Oct 30;154(2):271–278. [PubMed]
  • Hanahan D. Dissecting multistep tumorigenesis in transgenic mice. Annu Rev Genet. 1988;22:479–519. [PubMed]
  • Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell. 1991 May 31;65(5):753–763. [PubMed]
  • Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249–270. [PubMed]
  • Johnson DE, Lee PL, Lu J, Williams LT. Diverse forms of a receptor for acidic and basic fibroblast growth factors. Mol Cell Biol. 1990 Sep;10(9):4728–4736. [PMC free article] [PubMed]
  • Keegan K, Johnson DE, Williams LT, Hayman MJ. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1095–1099. [PMC free article] [PubMed]
  • Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. [PubMed]
  • Leder A, Pattengale PK, Kuo A, Stewart TA, Leder P. Consequences of widespread deregulation of the c-myc gene in transgenic mice: multiple neoplasms and normal development. Cell. 1986 May 23;45(4):485–495. [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]
  • Mangues R, Seidman I, Pellicer A, Gordon JW. Tumorigenesis and male sterility in transgenic mice expressing a MMTV/N-ras oncogene. Oncogene. 1990 Oct;5(10):1491–1497. [PubMed]
  • Matsui Y, Halter SA, Holt JT, Hogan BL, Coffey RJ. Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice. Cell. 1990 Jun 15;61(6):1147–1155. [PubMed]
  • Mester J, Wagenaar E, Sluyser M, Nusse R. Activation of int-1 and int-2 mammary oncogenes in hormone-dependent and -independent mammary tumors of GR mice. J Virol. 1987 Apr;61(4):1073–1078. [PMC free article] [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]
  • Nusse R, Brown A, Papkoff J, Scambler P, Shackleford G, McMahon A, Moon R, Varmus H. A new nomenclature for int-1 and related genes: the Wnt gene family. Cell. 1991 Jan 25;64(2):231–231. [PubMed]
  • Nusse R, Theunissen H, Wagenaar E, Rijsewijk F, Gennissen A, Otte A, Schuuring E, van Ooyen A. The Wnt-1 (int-1) oncogene promoter and its mechanism of activation by insertion of proviral DNA of the mouse mammary tumor virus. Mol Cell Biol. 1990 Aug;10(8):4170–4179. [PMC free article] [PubMed]
  • Nusse R, van Ooyen A, Cox D, Fung YK, 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. [PubMed]
  • Nusse R, Varmus HE. 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. [PubMed]
  • Ornitz DM, Moreadith RW, Leder P. Binary system for regulating transgene expression in mice: targeting int-2 gene expression with yeast GAL4/UAS control elements. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):698–702. [PMC free article] [PubMed]
  • Palmiter RD, Brinster RL. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465–499. [PubMed]
  • Papkoff J, Brown AM, Varmus HE. The int-1 proto-oncogene products are glycoproteins that appear to enter the secretory pathway. Mol Cell Biol. 1987 Nov;7(11):3978–3984. [PMC free article] [PubMed]
  • Papkoff J, Schryver B. Secreted int-1 protein is associated with the cell surface. Mol Cell Biol. 1990 Jun;10(6):2723–2730. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Peters G, Brookes S, Smith R, Placzek M, Dickson C. The mouse homolog of the hst/k-FGF gene is adjacent to int-2 and is activated by proviral insertion in some virally induced mammary tumors. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5678–5682. [PMC free article] [PubMed]
  • Peters G, Lee AE, 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. [PubMed]
  • Rijsewijk F, van Deemter L, Wagenaar E, Sonnenberg A, Nusse R. Transfection of the int-1 mammary oncogene in cuboidal RAC mammary cell line results in morphological transformation and tumorigenicity. EMBO J. 1987 Jan;6(1):127–131. [PMC free article] [PubMed]
  • Roelink H, Wagenaar E, Lopes da Silva S, Nusse R. Wnt-3, a gene activated by proviral insertion in mouse mammary tumors, is homologous to int-1/Wnt-1 and is normally expressed in mouse embryos and adult brain. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4519–4523. [PMC free article] [PubMed]
  • Roop DR, Krieg TM, Mehrel T, Cheng CK, Yuspa SH. Transcriptional control of high molecular weight keratin gene expression in multistage mouse skin carcinogenesis. Cancer Res. 1988 Jun 1;48(11):3245–3252. [PubMed]
  • Ruley HE. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983 Aug 18;304(5927):602–606. [PubMed]
  • Singer PA, Trevor K, Oshima RG. Molecular cloning and characterization of the Endo B cytokeratin expressed in preimplantation mouse embryos. J Biol Chem. 1986 Jan 15;261(2):538–547. [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]
  • Smith GH, Mehrel T, Roop DR. Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium. Cell Growth Differ. 1990 Apr;1(4):161–170. [PubMed]
  • Smith R, Peters G, Dickson C. Multiple RNAs expressed from the int-2 gene in mouse embryonal carcinoma cell lines encode a protein with homology to fibroblast growth factors. EMBO J. 1988 Apr;7(4):1013–1022. [PMC free article] [PubMed]
  • Stewart TA, Pattengale PK, Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell. 1984 Oct;38(3):627–637. [PubMed]
  • Tremblay PJ, Pothier F, Hoang T, Tremblay G, Brownstein S, Liszauer A, Jolicoeur P. Transgenic mice carrying the mouse mammary tumor virus ras fusion gene: distinct effects in various tissues. Mol Cell Biol. 1989 Feb;9(2):854–859. [PMC free article] [PubMed]
  • Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell. 1988 Nov 18;55(4):619–625. [PubMed]
  • van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T, Berns A. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989 Feb 24;56(4):673–682. [PubMed]
  • van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 1991 May 31;65(5):737–752. [PubMed]
  • 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. [PubMed]
  • Verbeek S, van Lohuizen M, van der Valk M, Domen J, Kraal G, Berns A. Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally. Mol Cell Biol. 1991 Feb;11(2):1176–1179. [PMC free article] [PubMed]
  • Weinberg RA. The action of oncogenes in the cytoplasm and nucleus. Science. 1985 Nov 15;230(4727):770–776. [PubMed]

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