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

Abstract

BackgroundBasal-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/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, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5ΔNβcat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers.MethodsMicroarray analysis was used to compare K5ΔNβcat 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 K5ΔNβcat mice. Stem cell amplification in K5ΔNβcat mouse mammary epithelium was assessed with 3D-culture and transplantation assays.ResultsHistological and microarray analyses of the mammary lesions of K5ΔNβcat 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 K5ΔNβcat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5ΔNβcat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5ΔNβcat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis.ConclusionsThese results strongly indicate that β-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.

The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division

“…A similar abundance in ribosomal proteins is also present in the Myc signature, consistent with its role in driving ribosomal biogenesis and protein translation in the mammary gland, among other tissues, and in cancer (87, 88). Because Myc is a critical factor for mammary stem cell identity and function (85), our results would suggest APT1 has a role in translation in mammary stem cells. What remains unclear is whether altering APT1 protein amounts induces the expansion of a population of cells expressing a mammary stem cell transcriptional signature or induces a de novo transcriptional signature in most cells.…”

Tobacco nitrosamine NNK increases ALDH-positive cells via ROS-Wnt signaling pathway in A549 human lung cancer cells

“…Myc is a potential candidate based on a recent report that suggests the involvement of Myc in β-catenin-mediated breast tumorigenesis (Moumen et al, 2013). Moreover, the induction of lung carcinogenesis is also reported to be associated with high Myc expression (Giri et al, 1997).…”

Mammary stem cells and the differentiation hierarchy: current status and perspectives

“…Indeed, p63 and Notch were found to have opposing roles in mammary epithelial cells: DN-p63 maintains a basal cell fate, while Notch signaling down-regulates p63 expression prior to luminal lineage commitment (Yalcin-Ozuysal et al 2010), a restriction point where Notch1 and Notch3 play a crucial role (Bouras et al 2008;Raouf et al 2008). Other potential transcriptional regulators of MaSCs include the transcription factors Stat3, CCAAT/enhancer-binding protein-b, and c-myc, all of which affect mammary repopulating ability in vivo (LaMarca et al 2010;Staniszewska et al 2012;Moumen et al 2013). Conversely, the tumor suppressor p53 serves a critical role in restricting the renewal of MaSCs and regulating their asymmetric division (Cicalese et al 2009;Chiche et al 2013).…”