期刊
EMBO REPORTS
卷 22, 期 12, 页码 -出版社
WILEY
DOI: 10.15252/embr.202153201
关键词
breast cancer; LRP6; miR-424/503; Wnt/beta-catenin
资金
- NY-state breast cancer grant program [DOH01-ROWLY6-2021-00045-C36613GG]
- JGW-Patterson Foundation [30015.088.072PA/IXS]
- Instituto de Salud Carlos III (ISCIII) [CP17/00063, MS17/00063]
- Ministerio de Ciencia, Innovacio'n y Universidades Gobierno de Espana [RyC-2016-19671, RTI2018-095611-A-I00]
- National Cancer Institute (NCI) of the National Institutes of Health (NIH) [F31CA232691]
The miR-424/503 cluster plays a crucial role in regulating Wnt signaling, MaSC fate, and breast cancer development, with its function involving targeting the LRP6 co-receptor to reduce its expression.
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/beta-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/beta-catenin signaling. Importantly, we show a strong association between miR-424/503 deletion and breast cancers with high levels of Wnt/beta-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.
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