Signaling Pathway Preferentially Induces Mammary Cancers from Progenitor Cells

Bryan Welm and Zena Werb, Ph.D.
University of California San Francisco
T32ES07106

Background: Breast cancer is a complex disease that arises from a variety of cellular alterations with different clinical manifestations. The contributions of different target cells and different cancerous mutations are not well understood. These investigators 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. Wnt proteins are a family of signaling molecules that regulate cell-to-cell interactions during embryogenesis.

Advance: Results of their experiments show that expression of the Wnt-1 protooncogene in mammary glands of transgenic mice causes growth of a population of epithelial cells expressing stem cell markers, keratin 6 and Sca-1. Resulting tumors also express these markers and contain epithelial and myoepithelial tumor cells that share a secondary mutation, loss of Pten, suggesting that these cells arose from a common progenitor. Mammary tumors arising in transgenic mice expressing -catenin and c-Myc, downstream components of the Wnt signaling pathway, also contain a significant proportion of myoepithelial cells and cells expressing keratin 6. These results suggest that mammary stem cells and/or progenitors to mammary 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 differing effects of oncogenes on distinct cell types in the breast.

Implication: These studies provide evidence suggesting components of the Wnt signaling pathway transform mammary stem cells, and that these cells develop into various tumors containing different cell types expressing markers of both mature and immature epithelial cells. Thus, breast cancer heterogeneity may result from transformation of distinct cell types by different oncogenes.

Citation: Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM, Varmus HE. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15853-8. Epub 2003 Dec 10.