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J. Biol. Chem., Vol. 281, Issue 46, 35081-35087, November 17, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/46/35081    most recent M607571200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lindvall, C. Articles by Williams, B. O. Search for Related Content PubMed PubMed Citation Articles by Lindvall, C. Articles by Williams, B. O. Social Bookmarking                      What's this?

The Wnt Signaling Receptor Lrp5 Is Required for Mammary Ductal Stem Cell Activity and Wnt1-induced Tumorigenesis^*

Charlotta Lindvall, Nicole C. Evans, Cassandra R. Zylstra, Yi Li, Caroline M. Alexander^¶1, and Bart O. Williams²

From the Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, Michigan 49503, the Breast Center, Baylor College of Medicine, Houston, Texas 77030, and the ^¶McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

Canonical Wnt signaling has emerged as a critical regulatory pathway for stem cells. The association between ectopic activation of Wnt signaling and many different types of human cancer suggests that Wnt ligands can initiate tumor formation through altered regulation of stem cell populations. Here we have shown that mice deficient for the Wnt co-receptor Lrp5 are resistant to Wnt1-induced mammary tumors, which have been shown to be derived from the mammary stem/progenitor cell population. These mice exhibit a profound delay in tumorigenesis that is associated with reduced Wnt1-induced accumulation of mammary progenitor cells. In addition to the tumor resistance phenotype, loss of Lrp5 delays normal mammary development. The ductal trees of 5-week-old Lrp5^-/- females have fewer terminal end buds, which are structures critical for juvenile ductal extension presumed to be rich in stem/progenitor cells. Consequently, the mature ductal tree is hypomorphic and does not completely fill the fat pad. Furthermore, Lrp5^-/- ductal cells from mature females exhibit little to no stem cell activity in limiting dilution transplants. Finally, we have shown that Lrp5^-/- embryos exhibit substantially impaired canonical Wnt signaling in the primitive stem cell compartment of the mammary placodes. These findings suggest that Lrp5-mediated canonical signaling is required for mammary ductal stem cell activity and for tumor development in response to oncogenic Wnt effectors.

Received for publication, August 9, 2006 , and in revised form, September 13, 2006.

^* This work was supported by the Van Andel Research Institute, National Institutes of Health RO1 CA113869-01 (to Y. L.), Susan G. Komen Breast Cancer Foundation Grant BCTR 0202106 (to C. M. A.), and a fellowship from the Wenner-Gren Foundation (to C. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence may be addressed: McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Ave. Madison, WI 53706. Tel.: 608-265-5182; Fax: 608-262-2824; E-mail: alexander{at}oncology.wisc.edu. ² To whom correspondence may be addressed: Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Inst., 333 Bostwick Ave. NE, Grand Rapids, MI 49504. Tel.: 616-234-5308; Fax: 616-234-5309; E-mail: Bart.Williams{at}vai.org.

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