MiR‐424/503 modulates Wnt/β‐catenin signaling in the mammary epithelium by targeting LRP6. (11th October 2021)

• Record Type: Journal Article
• Authors: Nekritz, Erin A; Rodriguez‐Barrueco, Ruth; Yan, Koon‐Kiu; Davis, Meredith L; Werner, Rachel L; Devis‐Jauregui, Laura; Mukhopadhyay, Partha; Yu, Jiyang; Llobet‐Navas, David; Silva, Jose
• Is Part Of: EMBO reports. Volume 22:Number 12(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-10-11
• Subjects: breast cancer -- LRP6 -- miR‐424/503 -- Wnt/β‐catenin; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202153201
• Languages: English
• ISSNs: 1469-221X

Abstract

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/β‐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/β‐catenin signaling. Importantly, we show a strong association between miR‐424/503 deletion and breast cancers with high levels of Wnt/β‐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. Synopsis: The miR‐424/503 cluster modulates canonical Wnt‐signaling in the mammary epithelium by targeting the LRP6 co‐receptor, unveiling a link between miR‐424/503, regulation of WNT‐signaling, mammary epithelial stem cell fate and tumorigenesis. Deletion of miR‐424/503 in mice generates mammary tumors with activated Wnt/β‐catenin. Deletion of miR‐424/503 is linked to activation of canonical Wnt‐signaling in human triple negative breast cancers. MiR‐424/503 expression influences mammary epithelial stem cell expansion dictated by ovarian cycles. MiR‐424/503 targets the LRP6 co‐receptor by binding to conserved binding sites in the 3'‐UTR of its mRNA. Abstract : The miR‐424/503 cluster modulates canonical Wnt‐signaling in the mammary epithelium by targeting the LRP6 co‐receptor, unveiling a link between miR‐424/503, regulation of WNT‐signaling, mammary epithelial stem cell fate and tumorigenesis.