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Lab of stem cell biology reveals the mechanism of Wnt/-catenin signaling pathway activation in triple negative breast cancer


Recently, stem cell biology group has revealed a new mechanism of Wnt/-catenin signaling pathway activation in triple-negative breast cancer. The research was published in Journal of Molecular Cell Biology as Cover story with the title of MiR-221/222 activate the Wnt/beta-catenin signaling to promote triple negative breast cancer.


Breast cancer is the most invasive cancer in women. Triple negative breast cancer (TNBC), characterized by the lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), is an aggressive form of cancer that conveys unpredictable and poor prognosis due to limited treatment options and lack of effectively targeted therapies. It accounts for approximately 15C20% of breast cancer patients. Although considerable progress has been made in breast cancer research, the mortality rate of TNBC has remained unchanged in the last decade primarily due to the lack of specific target.


Wnt/-catenin signaling is hyperactivated in TNBC, which promotes the progression of TNBC. However, the molecular mechanism of Wnt/-catenin activation in TNBC remains unknown. In this study, we report that TNBC cells over-express miR-221/222. Moreover, we demonstrate by both ex vivo and xenograft experiments that miR-221/222 overexpression promotes the proliferation, viability, epithelial-to-mesenchymal transition, and migration of breast cancer cells. MiR-221/222 achieved so by directly repressing multiple negative regulators of the Wnt/-catenin signaling pathway, including WIF1, SFRP2, DKK2, and AXIN2, to activate the pathway. Furthermore, we show that the level of miR-221/222 expression is inversely correlated with patients survival; whereas that of their target genes in the Wnt/-catenin pathway is positively correlated to the patients survival. Remarkably, anti-miR-221/222 significantly increase apoptosis with tamoxifen/Wnt3a treatment but not with cyclophosphamide/Wnt3a treatment. These results reveal the causal regulatory relationship between miR-221/222 and the Wnt signaling pathway as well as their critical roles in TNBC. In addition, our study offers a new entry point for TNBC treatment.


The main authors are Sanhong Liu Research Associate Professor, Zifeng Wang and Zukai Liu SIAIS graduate student. The corresponding author are Sanhong Liu and Haifan Lin. The work has been financed by NSFC.


Link to full paper: https://academic.oup.com/jmcb/article/10/4/302/5059631



Fig1. The cover of JMCB



 
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