A Mouse Model for Breast Cancer Induced by Amplification and Overexpression of the neu Promoter and Transgene

Abstract

Background: ErbB-2 is a critical oncogenic marker in human breast cancer. Its appearance correlates with poor prognosis and it is, therefore, an important target for physiologic investigation and therapeutic intervention. With this in mind, we have created and characterized two mouse breast cancer models that express rat wild type neu, the homologue of ErbB-2, and rat mutant neu under the control of the normal mouse neu promoter. These models in which the copy number of the neu gene is moderately amplified should more closely parallel the expression pattern of ErbB-2 seen in some cases of human breast cancer. Materials and Methods: Transgenic mouse models were constructed by injecting one of the two pronuclei of a fertilized FVB/n egg and implanting it into a pseudopregnant Swiss/Webster mouse. Tissue expression was analyzed through the use of reverse transcription polymerase chain reaction and mammary histopathology examined by fixing, staining and mounting of the entire gland. Results: In the former wild type model, we show that low level, long term expression of neu leads to abnormal lobuloalveolar development in virginal glands and incomplete regression in multiparous glands. Malignant foci form following multiple rounds of pregnancy and regression. In the latter model, a similarly directed transgene carrying the constitutively activated, mutant form of the rat neu gene, a stronger but similar phenotype is displayed. Conclusion: Evidently minor perturbations in amplified neu expression are sufficient to alter mammary development and induce malignant transformation.