Mammary Cells with Active Wnt Signaling Resist ErbB2-Induced Tumorigenesis

被引:9
作者
Bu, Wen [1 ,2 ]
Zhang, Xiang [1 ,2 ]
Dai, Hua [1 ,3 ]
Huang, Shixia [2 ]
Li, Yi [1 ,2 ]
机构
[1] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Yangzhou Univ, Sch Med, Dept Physiol, Yangzhou, Jiangsu, Peoples R China
来源
PLOS ONE | 2013年 / 8卷 / 11期
基金
美国国家卫生研究院;
关键词
WNT/BETA-CATENIN PATHWAY; MIDDLE T-ANTIGEN; STEM-CELLS; BREAST-CANCER; BETA-CATENIN; TRANSGENIC MICE; SELF-RENEWAL; EPITHELIAL-CELLS; PROGENITOR CELLS; EXPRESSION;
D O I
10.1371/journal.pone.0078720
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Aberrant activation of Wnt signaling is frequent in human malignancies. In normal epithelial tissues, including the breast, Wnt signaling is active only in a subset of cells, but it is unknown whether this subset of Wnt signaling-active cells is at increased risk of carcinogenesis. We created transgenic mice (TOP-tva) in which the synthetic Wnt-responsive promoter TOP controlled the gene encoding TVA, which confers susceptibility to infection by the retroviral vector RCAS. Thus, only cells in which Wnt signaling is active will express tva and be targeted by RCAS. Surprisingly, we found that RCAS-mediated delivery of cDNA encoding a constitutively activated version of ErbB2 (HER2/Neu) into the small number of TVA+ mammary epithelial cells in TOP-tva mice failed to induce tumor, while the same virus readily induced mammary tumors after it was delivered into a comparable number of cells in our previously reported mouse line MMTV-tva, whose tva is broadly expressed in mammary epithelium. Furthermore, we could not even detect any early lesions or infected cells in TOP-tva mice at the time of necropsy. Therefore, we conclude that the Wnt pathway-active cell subset in the normal mammary epithelium does not evolve into tumors following ErbB2 activation-rather, they apparently die due to apoptosis, an anticancer "barrier" that we have reported to be erected in some mammary cells followed ErbB2 activation. In accord with these mouse model data, we found that unlike the basal subtype, ErbB2+ human breast cancers rarely involve aberrant activation of Wnt signaling. This is the first report of a defined sub-population of mammalian cells that is "protected" from tumorigenesis by a potent oncogene, and provides direct in vivo evidence that mammary epithelial cells are not equal in their response to oncogene-initiated transformation.
引用
收藏
页数:9
相关论文
共 59 条
[1]   Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism [J].
Ayyanan, A ;
Civenni, G ;
Ciarloni, L ;
Morel, C ;
Mueller, N ;
Lefort, K ;
Mandinova, A ;
Raffoul, W ;
Fiche, M ;
Dotto, GP ;
Brisken, C .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (10) :3799-3804
[2]   The Wnt Receptor, Lrp5, Is Expressed by Mouse Mammary Stem Cells and Is Required to Maintain the Basal Lineage [J].
Badders, Nisha M. ;
Goel, Shruti ;
Clark, Rod J. ;
Klos, Kristine S. ;
Kim, Soyoung ;
Bafico, Anna ;
Lindvall, Charlotta ;
Williams, Bart O. ;
Alexander, Caroline M. .
PLOS ONE, 2009, 4 (08)
[3]   Crypt stem cells as the cells-of-origin of intestinal cancer [J].
Barker, Nick ;
Ridgway, Rachel A. ;
van Es, Johan H. ;
van de Wetering, Marc ;
Begthel, Harry ;
van den Born, Maaike ;
Danenberg, Esther ;
Clarke, Alan R. ;
Sansom, Owen J. ;
Clevers, Hans .
NATURE, 2009, 457 (7229) :608-U119
[4]   Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer [J].
Bu, W. ;
Chen, J. ;
Morrison, G. D. ;
Huang, S. ;
Creighton, C. J. ;
Huang, J. ;
Chamness, G. C. ;
Hilsenbeck, S. G. ;
Roop, D. R. ;
Leavitt, A. D. ;
Li, Y. .
ONCOGENE, 2011, 30 (43) :4399-4409
[5]   Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis [J].
Chu, EY ;
Hens, J ;
Andl, T ;
Kairo, A ;
Yamaguchi, TP ;
Brisken, C ;
Glick, A ;
Wysolmerski, JJ ;
Millar, SE .
DEVELOPMENT, 2004, 131 (19) :4819-4829
[6]   Wnt/β-Catenin Signaling and Disease [J].
Clevers, Hans ;
Nusse, Roel .
CELL, 2012, 149 (06) :1192-1205
[7]  
DasGupta R, 1999, DEVELOPMENT, V126, P4557
[8]   Polyoma virus middle T antigen and its role in identifying cancer-related molecules [J].
Dilworth, SM .
NATURE REVIEWS CANCER, 2002, 2 (12) :951-956
[9]   A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer [J].
DiMeo, Theresa A. ;
Anderson, Kristen ;
Phadke, Pushkar ;
Feng, Chang ;
Perou, Charles M. ;
Naber, Steven ;
Kuperwasser, Charlotte .
CANCER RESEARCH, 2009, 69 (13) :5364-5373
[10]   A transgenic Lef1/β-catenin-dependent reporter is expressed in spatially restricted domains throughout zebrafish development [J].
Dorsky, RI ;
Sheldahl, LC ;
Moon, RT .
DEVELOPMENTAL BIOLOGY, 2002, 241 (02) :229-237