Role of Endocrine, Autocrine, and Paracrine Interactions in the Development of Mammary Hyperplasia in Wnt-\ Transgenic Mice1

The Wnt-\ proto-oncogene is transcriptionally activated by mouse mammary tumor virus in mouse mammary tumor virus-induced tumors. Previous studies using transgenic mice showed that \\'nt-\ expression in mammary gland causes alveolar hyperplasias which resemble mam mary glands of pregnant mice. To understand the role of mammogenic hormones in the genesis of these hyperplasias, we examined the devel opment of these glands before puberty in young transgenic mice and the effects of ovariectomy and adrenalectomy on the growth and morphology of If nr 1 mammary hyperplasia. Mammary glands of H nr-1 transgenic females showed hyperplastic morphology as early as 1 week after birth. The normal structure of the uterus of the adult Wnt-l virgin mouse indicated that the circulating levels of ovarian hormones were not ele vated. Ovariectomy and adrenalectomy had no obvious effect on the morphology of these mammary hyperplasias. To assess possible paracrine stimulation of mammary epithelial cells (MEC) by stromal cells, we transplanted MEC from normal BALB/c mice into gland-free fat pads of If'nf-1 transgenic mice and found that normal MEC maintained their normal ductal structure in Wnt-\ fat pads without alveolar devel opment. Further, we did not detect lt'nt-l niRN.V expression in the gland-free fat pads of these transgenic mice. When II nr 1 MEC were transplanted into the fat pads of nude mice and allowed to grow towards existing normal MEC, the morphology of the existing normal MEC remained normal. We concluded that the development of mammary hyperplasia in Wnt-l transgenic mice is solely dependent on Wnt-\ expression in MEC. We speculate that Wnt-\ may be a growth factor for mammary gland that only acts locally on the cells that produce it.