Wnt-Induced Progenitors: Are They Highly Mutable?

Abstract : Dysregulated Wnt signaling is the cause of many human tumors, and induces breast cancer in mice. We have previously found that the initiating response to Wnt signaling is the accumulation of breast somatic stem cells. We propose that tumor development is related to this increase, and sought with this proposal to test whether the stem cells that arise in transgenic mice expressing Wnt effectors are more mutable than usual. This would explain why the preneoplastic glands invariably acquire mutagenic changes and progress to tumor development. In order to test this hypothesis, we cultured mammary clonagens (mammospheres) and proposed to test their mutability with chemical carcinogens. We found that, contrary to our prediction, mammospheres are almost completely absent in cultures of mammary epithelial cells that express Wnt effectors. Similarly, adherent clonagen numbers were reduced by 90%. We anticipated that their number would increase by 10-fold to reflect other results. We are investigating this phenomenon to determine whether this is due to inhibition of clonagen differentiation and expansion by ectopic Wnt signaling. This is likely to enable us to describe better the selective effects of Wnt signaling on mammary stem cells.