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Msi1 promotes breast cancer metastasis by regulating invadopodia-mediated extracellular matrix degradation via the Timp3–Mmp9 pathway

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Abstract

Metastasis is the main cause of death in breast cancer patients. The initial step of metastasis is invadopodia-mediated extracellular matrix (ECM) degradation, which enables local breast tumor cells to invade surrounding tissues. However, the molecular mechanism underlying invadopodia-mediated metastasis remains largely unknown. Here we found that the RNA-binding protein Musashi1 (Msi1) exhibited elevated expression in invasive breast tumors and promoted lung metastasis of mammary cancer cells. Suppression of Msi1 reduced invadopodia formation in mammary cancer cells. Furthermore, Msi1 deficiency decreased the expression and activity of Mmp9, an important enzyme in ECM degradation. Mechanistically, Msi1 directly suppressed Timp3, an endogenous inhibitor of Mmp9. In clinical breast cancer specimens, TIMP3 and MSI1 levels were significantly inversely correlated both in normal breast tissue and breast cancer tissues and associated with overall survival in breast cancer patients. Taken together, our findings demonstrate that the MSI1–TIMP3–MMP9 cascade is critical for invadopodia-mediated onset of metastasis in breast cancer, providing novel insights into a promising therapeutic strategy for breast cancer metastasis.

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Fig. 1: MSI1 expression is upregulated in invasive breast cancer.
Fig. 2: Msi1 depletion impairs lung metastasis of mammary tumor cells rather than tumor growth.
Fig. 3: Msi1 depletion reduces mammary tumor cell invasion and migration.
Fig. 4: Msi1 deficiency blocks invadopodia formation and inhibits Mmp9 expression and activity in mammary tumor cells.
Fig. 5: Msi1 directly suppresses Timp3 to regulate ECM degradation.
Fig. 6: Timp3 functionally mediated the promotive effects of Msi1 on breast cancer cell invasion and lung metastasis.
Fig. 7: TIMP3 expression is inversely correlated with MSI1 expression in human breast cancer.
Fig. 8: Schematic of the function and mechanism of Msi1 in breast cancer metastasis.

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Acknowledgements

This work is supported by the National Natural Science Foundation of China (Nos. 81772984, 81572614), Beijing Nature Foundation Grant (5162018), the Major Project for Cultivation Technology (2016ZX08008001, 2014ZX08008001), Basic Research Program (2019TC227, 2019TC088), and SKLAB Open Grant (2020SKLAB6-18). The authors thank the members of the laboratory animal center in China Agricultural University for their assistance in animal care.

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Correspondence to Li Zhao or Zhengquan Yu.

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Bi, X., Lou, P., Song, Y. et al. Msi1 promotes breast cancer metastasis by regulating invadopodia-mediated extracellular matrix degradation via the Timp3–Mmp9 pathway. Oncogene 40, 4832–4845 (2021). https://doi.org/10.1038/s41388-021-01873-8

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