Activation of different Wnt/β-catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors

Abstract

The Wnt/b-catenin signaling pathway controls cell fate and neoplastic transformation. Expression of an endogenous stabilized b-catenin (DE3 b-catenin) in mammary epithelium leads to the transdifferentiation into epidermis-and pilar-like structures. Signaling molecules in the canonical Wnt pathway upstream from b-catenin induce glandular tumors but it is not clear whether they also cause squamous transdifferentiation. To address this question we have now investigated mammary epithelium from transgenic mice that express activating molecules of the Wnt pathway: Wnt10b, Int2/Fgf3, CK2a, DE3 b-catenin, Cyclin D1, and dominant negative (dn) GSK3b. Cytokeratin 5 (CK5), which is expressed in both mammary myoepithelium and epidermis, and the epidermis-specific CK1 and CK6 were used as differentiation markers. Extensive squamous metaplasias and widespread expression of CK1 and CK6 were observed in DE3 b-catenin transgenic mammary tissue. Wnt10b and Int2 transgenes also induced squamous metaplasias, but expression of CK1 and CK6 was sporadic. While CK5 expression in Wnt10b transgenic tissue was still confined to the lining cell layer, its expression in Int2 transgenic tissue was completely disorganized. In contrast, cytokeratin expression in CK2a, dnGSK3b and Cyclin D1 transgenic mammary tissues was similar to that in DE3 bcatenin tissue. In support of transdifferentiation, expression of hard keratins specific for hair and nails was observed in pilar tumors. These results demonstrate that the activation of Wnt signaling components in mammary epithelium induces not only glandular tumors but also squamous differentiation, possibly by activating LEF-1, which is expressed in normal mammary epithelium.

The canonical NF-κB pathway is required for formation of luminal mammary neoplasias and is activated in the mammary progenitor population

“…MMTV-Wnt1 and MMTV-stable DNb-catenin transgenic mice develop multiple lobuloalveolar hyperplasias, a subset of which progresses to focal carcinomas and many pilar squamous (hair follicle-containing tumors) forms (Miyoshi et al, 2001 induced squamous metaplasias were not invasive and strongly expressed the basal cytokeratin CK6 but not ErbB2, features which were recently described in human squamous carcinoma of the breast (Grenier et al, 2007). They also contained cells positive for the basal cell and metaplasia marker, p63.…”

Stabilized β-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function

“…Alternatively, the loss of Foxn1 expression could also have occurred secondary to TECs adopting a new cell fate because enforced activation of canonical Wnt signaling has been demonstrated to effect transdifferentiation (57,58). In this context, it is possible that Wnts regulate the expression of downstream target genes whose functions are associated with positional fate assignment.…”

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

“…Therefore, upregulation of the AhR appears to be a characteristic of the transformation process. Interestingly, recent studies with prostate carcinoma cells suggest that high AhR levels may be driven by Wnt signaling (Chesire et al, 2004), a pathway implicated in malignant transformation (Miyoshi et al, 2002;Li et al, 2003). Furthermore, nuclear localization of the AhR in Hs578T cells and in other human tumor cell lines (Singh et al, 1996;Ge and Elferink, 1998;Hayashibara et al, 2003) suggests that the AhR may be transcriptionally active, despite the absence of exogenous ligands.…”