Lactation-induced WAP-SV40 Tag transgene expression in C57BL/6J mice leads to mammary carcinoma.

Abstract

Two transgenic lineages were generated by directing the expression of SV40 T antigen to the mammary gland of inbred C57BL/6J mice using the whey acidic protein (WAP) promoter. In one lineage, WAPTag 1, multiparous female mice developed mammary adenocarcinoma with an average latency period of 13 months. The histopathological phenotype was heterogeneous, tumours occurred in a stochastic fashion, normal tissue was located next to neoplastic tissue, the mammary tumours usually developed and were remarkably similar to that observed in human cases. In addition, male and virgin females developed a poorly differentiated SV40 T antigen-positive soft tissue sarcoma, also at 13 months of age. In the other lineage, WAPTag 3, some parous females developed mammary tumours, but most mice succumbed to osteosarcomas arising from the os petrosum at 5.5 to 6 months of age and on necropsy, renal adenocarcinomas were also found. Appearance of these unexpected tumour types demonstrates the non-specific expression of SV40 Tag under the control of the WAP promoter. The expression of SV40 Tag in mammary glands at different stages of development was also examined, and only actively lactating glands were positive. This suggests that the abundant cyclic synthesis of SV40 Tag associated with pregnancy is required for mammary tumorigenesis in these lineages.