A mouse mammary tumor virus Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha

Estrogens have important functions in mammary gland development and carcino genesis. To better define these roles, we have used two previously characte rized lines of genetically altered mice: estrogen receptor-or (ER alpha) kn ockout (ERKO) mice, which Lack the gene encoding ERa, and mouse mammary vir us tumor (MMTV)-Wnt-1 transgenic mice (Wnt-1 TG), which develop mammary hyp erplasia and neoplasia due to ectopic production of the Wnt-1 secretory gly coprotein. We have crossed these lines to ascertain the effects of ERa defi ciency on mammary gland development and carcinogenesis in mice expressing t he Wnt-1 transgene, Introduction of the Wnt-1 transgene into the ERKO backg round stimulates proliferation of alveolar-like epithelium, indicating that Wnt-1 protein can promote mitogenesis in the absence of an ER alpha-mediat ed response. The hyperplastic glandular tissue remains confined to the nipp le region, implying that the requirement for EP alpha in ductal expansion i s not overcome by ectopic Wnt-1, Tumors were detected in virgin ERKO female s expressing the Wnt-1 transgene at an average age (48 weeks) that is twice that seen in virgin Wnt-1 TG mice (24 weeks) competent to produce ER alpha . Prepubertal ovariectomy of Wnt-1 TG mice also extended tumor latency to 4 2 weeks. However, pregnancy did not appear to accelerate the appearance of tumors in Wnt-1 TG mice, and tumor growth rates were not measurably affecte d by Late ovariectomy. Small hyperplastic mammary glands were observed in W nt-1 TG males, regardless of ERa gene status; the glands were similar in ap pearance to those found in ERKO/Wnt-1 TG females. Mammary tumors also occur red in Wnt-1 TG males; latency tended to be Longer in the heterozygous ER a lpha and ERKO males (86 to 100 weeks) than in wild-type ERa mice (ca. 75 we eks). We conclude that ectopic expression of the Wnt-1 proto- oncogene can induce mammary hyperplasia and tumorigenesis in the absence of ER alpha in female and male mice. The delayed time of tumor appearance may depend on th e number of cells at risk of secondary events in the hyperplastic glands, o n the carcinogenesis-promoting effects of ER alpha signaling, or on both.