Mammary tumor induction in transgenic mice expressing an RNA-binding protein.
We have analyzed mammary tumors arising in transgenic mice expressing a novel, multifunctional RNA-binding protein. The protein, which we call the c-myc mRNA coding region instability determinant binding protein (CRD-BP), binds to c-myc, insulin-like growth factor II, and beta-actin mRNAs, and to H19 RNA. Depending on the RNA substrate, the CRD-BP affects RNA localization, translation, or stability. CRD-BP levels are high during fetal development but low or undetectable in normal adult tissues. The CRD-BP is linked to tumorigenesis, because its expression is reactivated in some adult human breast, colon, and lung tumors. These data suggest the CRD-BP is a proto-oncogene. To test this idea, the CRD-BP was expressed from the whey acidic protein (WAP) promoter in mammary epithelial cells of adult transgenic mice. The incidence of mammary tumors was 95% and 60% in two lines of WAP-CRD-BP mice with high and low relative CRD-BP expression, respectively. Some of the tumors metastasized. Nontransgenic mice did not develop mammary tumors. H19 RNA and insulin-like growth factor II mRNA were up-regulated significantly in non-neoplastic WAP-CRD-BP mammary tissue. WAP-CRD-BP mice are a novel model for mammary neoplasia and might provide insights into human breast cancer biology.
Tessier
Charles R
CR
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Doyle
Glenn A
GA
Clark
Brad A
BA
Pitot
Henry C
HC
Ross
Jeff
J
D020121:5' Untranslated Regions / Q000235:genetics; D000199:Actins / Q000235:genetics; D000367:Age Factors; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D017931:DNA Primers; D015342:DNA Probes; D004195:Disease Models, Animal; D005260:Female; D016259:Genes, myc; D005914:Globins / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins / Q000235:genetics*; D014981:Xenopus; D029867:Xenopus Proteins
D020121:5' Untranslated Regions; D000199:Actins; D017931:DNA Primers; D015342:DNA Probes; C498635:IGF2BP3 protein, Xenopus; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; D029867:Xenopus Proteins; D007335:Insulin-Like Growth Factor II; D005914:Globins