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 H1...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2004, Vol.64 (1), p.209-214
Main Authors: TESSIER, Charles R, DOYLE, Glenn A, CLARK, Brad A, PITOT, Henry C, ROSS, Jeff
Format: Article
Language:English
Subjects:
5' Untranslated Regions - genetics
Actins - genetics
Age Factors
Animals
Antineoplastic agents
Base Sequence
Biological and medical sciences
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Disease Models, Animal
DNA Primers
DNA Probes
Female
Genes, myc
Globins - genetics
Insulin-Like Growth Factor II - genetics
Mammary Neoplasms, Experimental - genetics
Mammary Neoplasms, Experimental - pathology
Medical sciences
Mice
Mice, Transgenic
Pharmacology. Drug treatments
Polymerase Chain Reaction
RNA-Binding Proteins - genetics
Tumors
Xenopus
Xenopus Proteins
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-03-2927