The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells

Ectopic activation of the Writ signaling pathway is highly oncogenic for many human tissues. Here, we show that ectopic Writ signaling increases the effective stem cell activity in mouse mammary glands in vivo. Furthermore, Writ effectors induce the accumulation of mouse mammary epithelial progenitors (assayed by Hoechst dye exclusion, a surrogate stem cell marker, side population cells) both in vivo and in vitro. The longevity of stem cells makes them good candidate tumor precursors, and we propose that Wnt-induced progenitor amplification is likely to be key to tumor initiation. In support of this notion, mammary glands from a tumor-resistant strain of mice (carrying a null mutation in syndecan-1) contain fewer side population cells. When this strain is crossed to mice that overexpress effectors of the beta-catenin/T cell factor Writ pathway, the amplification of progenitors is reduced, together with all subsequent events of tumor development. We propose that the growth dynamic of the stem cell fraction is a major determinant of tumor susceptibility.