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Role of Endocrine, Autocrine, and Paracrine Interactions in the Development of Mammary Hyperplasia in Wnt-1 Transgenic Mice¹

Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California at Berkeley, Berkeley, California 94720 [T-P. L., R. C. G., R. C. O., S. N.], and Division of Biology, University of California at Santa Cruz, Santa Cruz, California 95064 [G. T.]

The Wnt-1 proto-oncogene is transcriptionally activated by mouse mammary tumor virus in mouse mammary tumor virus-induced tumors. Previous studies using transgenic mice showed that Wnt-1 expression in mammary gland causes alveolar hyperplasias which resemble mammary glands of pregnant mice. To understand the role of mammogenic hormones in the genesis of these hyperplasias, we examined the development of these glands before puberty in young transgenic mice and the effects of ovariectomy and adrenalectomy on the growth and morphology of Wnt-1 mammary hyperplasia. Mammary glands of Wnt-1 transgenic females showed hyperplastic morphology as early as 1 week after birth. The normal structure of the uterus of the adult Wnt-1 virgin mouse indicated that the circulating levels of ovarian hormones were not elevated. 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 Wnt-1 transgenic mice and found that normal MEC maintained their normal ductal structure in Wnt-1 fat pads without alveolar development. Further, we did not detect Wnt-1 mRNA expression in the gland-free fat pads of these transgenic mice. When Wnt-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-1 transgenic mice is solely dependent on Wnt-1 expression in MEC. We speculate that Wnt-1 may be a growth factor for mammary gland that only acts locally on the cells that produce it.

¹ This study was supported by NIH Grant CA 05388.

² To whom requests for reprints should be addressed, at 491 LSA, Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94720.

Received 1/27/92. Accepted 6/ 4/92.

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