A novel model for breast cancer: Role of an RNA-binding protein in mammary development and tumorigenesis

The VICKZ family of RNA-binding proteins is involved in translation control, RNA localization and mRNA stability. I have studied one of the mouse members of this family which we call the c-myc Coding Region instability Determinant Binding Protein (CRD-BP). The CRD-BP is expressed in embryonic development, but is repressed shortly after birth. However, the gene is reactivated in many different human cancers. To determine whether or not the CRD-BP is a proto-oncogene, the protein was expressed in mammary epithelial cells of adult transgenic mice using the mouse whey acidic protein (WAP) promoter. WAP-CRD-BP mice developed mammary adenocarcinomas by approximately one year of age. Analysis of the tumors revealed many similarities between this model of mammary cancer and human breast cancer. For example, approximately 50% of WAP-CRD-BP induced tumors are estrogen receptor positive, which is similar to that seen in human breast cancer. Since the CRD-BP family members bind multiple RNAs, I analyzed the expression of the known RNA targets. H19 RNA and IGF-II mRNA were increased 10- and 100-fold, respectively, in transgenic mammary glands compared to wild-type controls. Microarray analysis revealed a 2 fold or more change in 76 known and unknown genes. Many of these changes are still under analysis. In addition, a separate line of transgenic mice which contains a CRD-BP transgene under the control of an inducible promoter was generated. These mice will provide valuable information on the dependence of CRD-BP induced mammary tumors on CRD-BP expression as well as facilitate analysis of the effects of CRD-BP expression on mammary morphogenesis. Both WAP-CRD-BP and inducible expression CRD-BP mice are novel models for mammary neoplasia and useful tools to study anti-cancer agents. Both may provide insights into human breast cancer biology.