Stem Cell Biology Lab’s Breast Cancer Research Cover Story in JMCB

ON2018-08-17TAG: ShanghaiTech UniversityCATEGORY: Published Research

Recently, SIAIS’s Stem Cell Biology Lab has revealed a new mechanism of Wnt/β-catenin signaling pathway activation in triple-negative breast cancer, which was published as a cover story in Journal of Molecular Cell Biology with the title "MiR-221/222 activate the Wnt/beta-catenin signaling to promote triple negative breast cancer."

Breast cancer is the most invasive type of 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 15–20% 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 a specific target.

Wnt/β-catenin signaling is hyperactivated in TNBC, which promotes the progression of TNBC. However, the molecular mechanism of Wnt/β-catenin activation in TNBC remains unknown. In this study, ShanghaiTech SIAIS scientists report that TNBC cells over-express miR-221/222. Moreover, they 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/β-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/β-catenin pathway is positively correlated with 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 Research Associate Professor Liu Sanhong and Wang Zifeng, along with SIAIS graduate student Liu Zukai. The corresponding authors are Liu Sanhong and Lin Haifan. Their work has been supported by NSFC and ShanghaiTech University.

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MiR-221/222 activate Wnt/β-catenin signaling pathway by directly repressing multiple negative regulators of the Wnt/β-catenin signaling pathway, including WIF1, SFRP2, DKK2, and AXIN2 in TNBC cells, thereby promoting the proliferation and metastasis of TNBC cells.