miR‐424/503 modulates Wnt/β‐catenin signaling in the mammary epithelium by targeting LRP6

Abstract

During the female lifetime, the expansion of the epithelium dictated by the ovarian cycles is supported by a transient increase in the mammary epithelial stem cell population (MaSCs). Notably, activation of Wnt/b-catenin signaling is an important trigger for MaSC expansion. Here, we report that the miR-424/503 cluster is a modulator of canonical Wnt signaling in the mammary epithelium. We show that mammary tumors of miR-424(322)/503-depleted mice exhibit activated Wnt/b-catenin signaling. Importantly, we show a strong association between miR-424/503 deletion and breast cancers with high levels of Wnt/b-catenin signaling. Moreover, miR-424/503 cluster is required for Wnt-mediated MaSC expansion induced by the ovarian cycles. Lastly, we show that miR-424/503 exerts its function by targeting two binding sites at the 3'UTR of the LRP6 co-receptor and reducing its expression. These results unveil an unknown link between the miR-424/503, regulation of Wnt signaling, MaSC fate, and tumorigenesis.

MicroRNAs in Molecular Classification and Pathogenesis of Breast Tumors

“…The overexpression of miR-93 promoted cellular differentiation and also determined the fate of normal and malignant MaSCs by downregulating the expression of multiple stem cell regulatory genes [ 55 ]. The miR-424/503 cluster, reportedly targeting the LRP6 co-receptor, works in tandem to regulate the mammary epithelial stem cell fate dictated by ovarian cycles and also drives tumorigenesis through modulating the canonical Wnt signaling [ 56 ]. The impact of an individual microRNA in regulating the expression of multiple gene targets occurs within the stem cell pool (e.g., miR-93 targets JAK1 , STAT3 , AKT3 , SOX4 , EZH1 and HMGA2 genes) [ 55 ] and in the de-differentiated tumor cells (e.g., miR-210 targets VEGF and RUNX3 gene; and miR-193 family targets CCND1 , PTEN , ER gene) [ 57 ].…”

Down-regulation of miR-424 inhibited the metastasis of endometrial carcinoma via targeting PTEN/PI3K/AKT signaling pathway

“…This indicates that miRNA is one of the largest regulatory gene families. Currently, the regulatory role of miRNAs in tumors has been widely reported 16 .…”