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

ABSTRACT: 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 overexpression. Recent studies have linked activation of the Wnt/?-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5?N?cat previously generated by our team present a constitutive activation of Wnt/?-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5?N?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?N?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?N?cat mice. Stem cell amplification in K5?N?cat mouse mammary epithelium was assessed with 3D-culture and transplantation assays. RESULTS: Histological and microarray analyses of the mammary lesions of K5?N?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?N?cat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5?N?cat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5?N?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 ?-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.

SUBMITTER: Moumen M

PROVIDER: S-EPMC4176121 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Moumen Mejdi M Chiche Aurélie A Decraene Charles C Petit Valérie V Gandarillas Alberto A Deugnier Marie-Ange MA Glukhova Marina A MA Faraldo Marisa M MM

Molecular cancer 20131030 1

<h4>Background</h4>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 overexpression. Recent studies have linked activation of the Wnt/β-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5ΔNβcat previously generated by our team present a constitutive activation of Wnt/β-catenin signaling in the basal myoepithelial cell layer, resu ...[more]

PMID: 24171719

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Project description:Our previous studies demonstrated that selective overexpression of the Ron receptor tyrosine kinase in the murine mammary epithelium leads to mammary tumor formation. Biochemical analysis of mammary tumor lysates showed that Ron overexpression was associated with increases in ?-catenin expression and tyrosine phosphorylation. ?-Catenin has also been shown to be regulated through tyrosine phosphorylation by the receptor tyrosine kinases Met, Fer and Fyn. However, the molecular and physiological roles of ?-catenin and ?-catenin tyrosine phosphorylation downstream of Ron are not known. To investigate this association, we show that Ron and ?-catenin are coordinately elevated in human breast cancers. Our data also demonstrate that activation of Ron, through ligand binding by hepatocyte growth factor-like protein (HGFL), induces the tyrosine phosphorylation of ?-catenin, primarily on tyrosine residues Tyr 654 and Tyr 670. In addition, HGFL-mediated Ron activation induces both ?-catenin nuclear localization and transcriptional activity, with Tyr 654 and Tyr 670 residues of ?-catenin being critical for these processes. We also demonstrate that a knockdown of Ron in breast cancer cell lines leads to a loss of HGFL-induced ?-catenin-dependent transcriptional activation and cell growth, which can be rescued by activation of canonical Wnt/?-catenin signaling. Moreover, we show that HGFL-dependent Ron activation mediates upregulation of the ?-catenin target genes cyclin D1 and c-myc, and that expression of these target genes in breast cancer cells is decreased following inhibition of Ron and/or ?-catenin. Finally, we show that genetic ablation of ?-catenin in Ron-expressing breast cancer cells decreases cellular proliferation in vitro, as well as mammary tumor growth and metastasis, following orthotopic transplantation into the mammary fat pad. Together, our data suggest that ?-catenin is a crucial downstream regulator of Ron receptor activation and is an important mediator of mammary tumorigenesis.

Dataset Information

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

Publications

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

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