Graduate School, Department of Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.
Molecular Mechanisms and Experimental Therapy in Oncology-Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
EMBO Rep. 2021 Dec 6;22(12):e53201. doi: 10.15252/embr.202153201. Epub 2021 Oct 11.
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.
在女性一生中，由卵巢周期决定的上皮细胞扩张得到乳腺上皮干细胞群体（MaSCs）的短暂增加的支持。值得注意的是，Wnt/β-catenin 信号的激活是 MaSC 扩增的重要触发因素。在这里，我们报告 miR-424/503 簇是乳腺上皮中经典 Wnt 信号的调节剂。我们表明，miR-424(322)/503 缺失的小鼠的乳腺肿瘤表现出激活的 Wnt/β-catenin 信号。重要的是，我们发现 miR-424/503 缺失与具有高水平 Wnt/β-catenin 信号的乳腺癌之间存在强烈关联。此外，miR-424/503 簇对于由卵巢周期诱导的 Wnt 介导的 MaSC 扩增是必需的。最后，我们表明 miR-424/503 通过靶向 LRP6 共受体 3'UTR 上的两个结合位点并降低其表达来发挥作用。这些结果揭示了 miR-424/503、Wnt 信号调节、MaSC 命运和肿瘤发生之间未知的联系。
