Wnt reaches out to Lin28 and let-7 Free

The canonical Wnt–β-catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This pathway can regulate mammary stem cell self-renewal and differentiation, yet despite being a key regulator of breast cancer stem cells, little is known about the downstream transcriptional cascade that is involved in this process. Here (p. 2877), Bo-An Li and colleagues use a microarray screening assay to identify novel downstream target microRNAs (miRNAs) of the Wnt–β-catenin pathway. Interestingly, the authors identify let-7 miRNAs, which have been shown to have an important function in breast cancer stem cells, as a target. Expression studies showed that whereas mature let-7 miRNAs are suppressed by the Wnt–β-catenin pathway, the primary transcripts are not, suggesting a post-transcriptional regulation of let-7 expression. The authors also identify Lin28, a negative regulator of let-7 biogenesis, as a direct downstream target. Accordingly, loss of function of Lin28 impaired inhibition of let-7 mediated by the Wnt–β-catenin pathway, and the expansion of breast cancer stem cells; moreover, this expansion was blocked by enforced expression of let-7. The authors further show that the Wnt–β-catenin pathway upregulates Lin28 and downregulates let-7 in both human breast cancer tissue samples and mouse tumour models. These findings, showing that the Wnt–β-catenin pathway, Lin28 and let-7 miRNAs connect in a signalling cascade, make an important contribution towards understanding the role of Wnt signalling in breast cancer stem cell biology.