Myc is required for β-catenin-mediated mammary stem cell amplification and tumorigenesis

Background: Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 ov erexpression. Recent studies have linked activation of the Wnt/beta-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5 Delta N beta cat previously generated by our team present a constitutive activation of Wnt/beta-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5 Delta N beta cat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers. Methods: Microarray analysis was used to compare K5 Delta N beta cat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5 Delta N beta cat mice. Stem cell amplification in K5 Delta N beta cat mouse mammary epithelium was assessed with 3D-culture and transplantation assays. Results: Histological and microarray analyses of the mammary lesions of K5 Delta N beta cat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5 Delta N beta cat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5 Delta N beta cat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5 Delta N beta cat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis. Conclusions: These results strongly indicate that beta-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors.