The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis

被引:129
作者
Lindvall, Charlotta
Evans, Nicole C.
Zylstra, Cassandra R.
Li, Yi
Alexander, Caroline M.
Williams, Bart O.
机构
[1] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA
[2] Van Andel Res Inst, Lab Cell Signaling & Carcinogenesis, Grand Rapids, MI 49503 USA
[3] Baylor Coll Med, Breast Ctr, Houston, TX 77030 USA
关键词
D O I
10.1074/jbc.M607571200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:35081 / 35087
页数:7
相关论文
共 43 条
[11]   Think globally, act locally: the making of a mouse mammary gland [J].
Hennighausen, L ;
Robinson, GW .
GENES & DEVELOPMENT, 1998, 12 (04) :449-455
[12]   Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6 [J].
Holmen, SL ;
Giambernardi, TA ;
Zylstra, CR ;
Buckner-Berghuis, BD ;
Resau, JH ;
Hess, JF ;
Glatt, V ;
Bouxsein, ML ;
Ai, MR ;
Warman, ML ;
Williams, BO .
JOURNAL OF BONE AND MINERAL RESEARCH, 2004, 19 (12) :2033-2040
[13]   Impaired mammary gland and lymphoid development caused by inducible expression of Axin in transgenic mice [J].
Hsu, W ;
Shakya, R ;
Costantini, F .
JOURNAL OF CELL BIOLOGY, 2001, 155 (06) :1055-1064
[14]   β-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin [J].
Huelsken, J ;
Vogel, R ;
Erdmann, B ;
Cotsarelis, G ;
Birchmeier, W .
CELL, 2001, 105 (04) :533-545
[15]   ΔN89β-catenin induces precocious development, differentiation, and neoplasia in mammary gland [J].
Imbert, A ;
Eelkema, R ;
Jordan, S ;
Feiner, H ;
Cowin, P .
JOURNAL OF CELL BIOLOGY, 2001, 153 (03) :555-568
[16]   TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth [J].
Inoki, Ken ;
Ouyang, Hongjiao ;
Zhu, Tianqing ;
Lindvall, Charlotta ;
Wang, Yian ;
Zhang, Xiaojie ;
Yang, Qian ;
Bennett, Christina ;
Harada, Yuko ;
Stankunas, Kryn ;
Wang, Cun-yu ;
He, Xi ;
MacDougald, Ormond A. ;
You, Ming ;
Williams, Bart O. ;
Guan, Kun-Liang .
CELL, 2006, 126 (05) :955-968
[17]  
Kenney Nicholas J., 2001, Journal of Biomedicine and Biotechnology, V1, P133, DOI 10.1155/S1110724301000304
[18]   Identification of bronchioalveolar stem cells in normal lung and lung cancer [J].
Kim, CFB ;
Jackson, EL ;
Woolfenden, AE ;
Lawrence, S ;
Babar, I ;
Vogel, S ;
Crowley, D ;
Bronson, RT ;
Jacks, T .
CELL, 2005, 121 (06) :823-835
[19]  
Klopocki E, 2004, INT J ONCOL, V25, P641
[20]  
Kordon EC, 1998, DEVELOPMENT, V125, P1921