Hormone-Dependent Uterine Adenocarcinoma Following Developmental Treatment with Diethylstilbestrol: A Murine Model for Hormonal Carcinogenesis

Estrogens have been associated with neoplasia in target tissues including cervix, uterus, ovary, and breast. The mechanisms underlying this association are probably varied. Recently, a model was reported for study of target organ specific hormonal carcinogenesis in which outbred newborn mice were treated with diethylstilbestrol (DES) on days 1–5 of age. Uterine tumors were observed in a time- and dose-related manner; at 18 months of age, cancers were seen in 90% of the mice exposed to 2 µg/pup/day of DES, but not in the corresponding controls. These tumors were hormone-dependent, since regression occurred when mice with established uterine tumors were ovariectomized. Estrogen treatment reestablished the growth of the lesions. In addition, when neonatally DES-treated mice were prepubertally ovariectomized, and therefore deficient in endogenous estrogen, no uterine tumors developed. Transplants of uterine tumor fragments were successfully grown and serially carried in castrated male nude mice. Like the primary tumors, these transplants required estrogen for maintenance and growth. Many of the transplanted tissues and primary lesions retained some differentiated functions such as the production of lactoferrin, an estrogen inducible uterine protein. In addition, estrogen receptor was detected by immunocytochemistry in both transplants and primary tumors. Cell lines have now been established from these DES-induced tumors, and subsequent experiments will provide the basis for studies in mechanisms of hormonal carcinogenesis, including the role of the estrogen receptor and the shift of tumors from hormone-dependent to independent status.