Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells

Li, Y., Welm, B., Podsypanina, K., Huang, S., Chamorro, M., Zhang, X., Rowlands, T., Egeblad, M., Cowin, P., Werb, Z., Tan, L. K., Rosen, J. M., Varmus, H. E. (2003) Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 100 (26). pp. 15853-15858. ISSN 00278424 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/14668450
DOI: 10.1073/pnas.2136825100

Abstract

Breast cancer is a genetically and clinically heterogeneous disease, and the contributions of different target cells and different oncogenic mutations to this heterogeneity are not well understood. Here we report that mammary tumors induced by components of the Wnt signaling pathway contain heterogeneous cell types and express early developmental markers, in contrast to tumors induced by other signaling elements. Expression of the Wnt-1 protooncogene in mammary glands of transgenic mice expands a population of epithelial cells expressing progenitor cell markers, keratin 6 and Sca-1; subsequent tumors express these markers and contain luminal epithelial and myoepithelial tumor cells that share a secondary mutation, loss of Pten, implying that they arose from a common progenitor. Mammary tumors arising in transgenic mice expressing β-catenin and c-Myc, downstream components of the canonical Wnt signaling pathway, also contain a significant proportion of myoepithelial cells and cells expressing keratin 6. Progenitor cell markers and myoepithelial cells, however, are lacking in mammary tumors from transgenic mice expressing Neu, H-Ras, or polyoma middle T antigen. These results suggest that mammary stem cells and/or progenitors to mammary luminal epithelial and myoepithelial cells may be the targets for oncogenesis by Wnt-1 signaling elements. Thus, the developmental heterogeneity of different breast cancers is in part a consequence of differential effects of oncogenes on distinct cell types in the breast.

Item Type: Paper
Uncontrolled Keywords: ataxin 1 beta catenin epidermal growth factor receptor 2 gene product keratin keratin 6 Myc protein phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase protein h ras unclassified drug virus middle T antigen Wnt protein animal cell animal tissue article breast carcinogenesis breast carcinoma cancer cell cell population cell type disease marker epithelium cell female gene mutation mouse myoepithelium cell nonhuman priority journal protein depletion protein expression proto oncogene signal transduction stem cell target cell transgene Animals Cytoskeletal Proteins Genes, myc Mammary Neoplasms, Experimental Mammary Tumor Virus, Mouse Mice Mice, Transgenic Mutation Proto-Oncogene Proteins Stem Cells Trans-Activators Wnt Proteins Wnt1 Protein Zebrafish Proteins Animalia Mus musculus
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Egeblad lab
Depositing User: Matt Covey
Date: 2003
Date Deposited: 14 Mar 2013 19:55
Last Modified: 14 Mar 2013 19:55
PMCID: PMC307657
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27806

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