title: Cancer stemness in Wnt-driven mammary tumorigenesis.
abstract: Wnt signaling plays a central role in mammary stem cell (MaSC) homeostasis and in breast cancer. In particular, epigenetic alterations at different members of the Wnt pathway have been identified among triple-negative, basal-like breast cancers. Previously, we developed a mouse model for metaplastic breast adenocarcinoma, a subtype of triple-negative breast cancer, by targeting a hypomorphic mutations in the endogenous Apc gene (Apc (1572T/+)). Here, by employing the CD24 and CD29 cell surface antigens, we have identified a subpopulation of mammary cancer stem cells (MaCSCs) from Apc (1572T/+) capable of self-renewal and differentiation both in vivo and in vitro. Moreover, immunohistochemical analysis of micro- and macrolung metastases and preliminary intravenous transplantation assays suggest that the MaCSCs underlie metastasis at distant organ sites. Expression profiling of the normal and tumor cell subpopulations encompassing MaSCs and CSCs revealed that the normal stem cell compartment is more similar to tumor cells than to their own differentiated progenies. Accordingly, Wnt signaling appears to be active in both the normal and cancer stem cell compartments, although at different levels. By comparing normal with cancer mouse mammary compartments, we identified a MaCSC gene signature able to predict outcome in breast cancer in man. Overall, our data indicate that constitutive Wnt signaling activation affects self-renewal and differentiation of MaSCs leading to metaplasia and basal-like adenocarcinomas.
authors: Department of Pathology, Josephine Nefkens Institute, Erasmus MC 3000 CA Rotterdam, The Netherlands and.
authors: Joana
authors: J
authors: Monteiro
authors: Claudia
authors: C
authors: Gaspar
authors: Wilfrid
authors: W
authors: Richer
authors: Patrick F
authors: PF
authors: Franken
authors: Andrea
authors: A
authors: Sacchetti
authors: Rosalie
authors: R
authors: Joosten
authors: Anouar
authors: A
authors: Idali
authors: Joana
authors: J
authors: Brandao
authors: Charles
authors: C
authors: Decraene
authors: Riccardo
authors: R
authors: Fodde
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality; D051927:CD24 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011237:Predictive Value of Tests; D012016:Reference Values; D059467:Transcriptome; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D019012:Integrin beta1; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse