A mouse model for breast cancer induced by amplification and overexpression of the neu promoter and transgene

Background: ErbB-2 is a critical oncogenic marker in human breast cancer. I ts appearance correlates with poor prognosis and it is, therefore, an impor tant target for physiologic investigation and therapeutic intervention. Wit h this in mind, we have created and characterized two mouse breast cancer m odels that express rat wild type neu, the homologue of ErB-2, and rat mutan t neu under the control of the normal mouse neu promoter. These models in w hich the copy number of the neu gene is moderately amplified should more cl osely parallel the expression pattern of ErbB-2 seen in some cases of human breast cancer. Materials and Methods: Transgenic mouse models were constructed by injectin g one of the two pronuclei of a fertilized FVB/n egg and implanting it into a pseudopregnant Swiss/Webster mouse. Tissue expression was analyzed throu gh the use of reverse transcription polymerase chain reaction and mammary h istopathology examined by fixing, staining and mounting of the entire gland . Results: In the former wild type model, we show that low level, long term e xpression of neu leads to abnormal lobuloalveolar development in virginal g lands 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, muta nt form of the rat neu gene, a stronger but similar phenotype is displayed. Conclusion: Evidently minor perturbations in amplified neu expression are s ufficient to alter mammary development and induce malignant transformation.