Survivin, a unique member of the IAP protein family, serves as a dual regulator of cell division and apoptosis18. Moreover, elevated mitochondrial fission was associated with poorer prognosis in TNBC patients. Mitochondrial fission promoted the survival of TNBC cells both in vitro and in vivo. Furthermore, we identified a positive feedback loop between mitochondrial fission and Notch signaling pathway in TNBC cells, as proved by the experimental evidence that the activation of Notch signaling enhanced Drp1-mediated mitochondrial fission and Drp1-mediated mitochondrial fission in turn promoted the activation of Notch signaling, which ultimately promoted the cell survival of TNBC via increasing survivin expression level. Inhibition of either Notch1 or Drp1 significantly impaired the activation of the other, leading to the suppression of TNBC cell survival and proliferation. Collectively, our data reveal a novel mechanism that the positive feedback loop between mitochondrial fission and Notch signaling promotes the survival, proliferation and apoptotic resistance of TNBC cells via increasing survivin expression and thus favors cancer progression. Introduction Breast cancer is one of the most common cancer that affects womens health worldwide1,2. Triple negative breast cancer (TNBC) is a subgroup typically characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Among breast cancer, TNBC is the most difficult to treat, due to its highly aggressive phenotype, low responsiveness to chemotherapeutic reagents, high rate of recurrence, and poor prognosis3,4. Therefore, there is an urgent medical need to identify therapeutic targets and develop more effective treatment strategies for TNBC. Encouragingly, emerging data have highlighted some promising molecular therapeutic targets for TNBC, including EGFR, PARP1, mTOR, TGF-, Notch signaling, Wnt/-catenin and Hedgehog pathways3,5. However, the detailed molecular mechanisms by which these pathways affect the TNBC development and progression remain unclear. Notch signaling pathway is an evolutionarily conserved signaling pathway that regulates stem cell Mesna maintenance, cell fate specification, differentiation, proliferation, motility and survival3,5,6. In Mesna mammals, the Notch signaling pathway consists of five ligands (Delta-like proteins 1/3/4, Jagged 1/2) and four receptors (Notch1/2/3/4). After the binding of Notch receptors and ligands, Notch is cleaved by a class of enzymes, resulting in the release of active NICD, which is an initiation of notch downstream signaling7. Numerous studies have demonstrated that Notch signaling pathway is frequently activated in many types of malignancies and confers a survival advantage on cancer cells, leading to poor clinical outcomes in patients8C12. In invasive breast cancer, the elevated expression of Notch signaling members, including Notch receptors and ligands and target molecules has been reported. In addition, it has been reported that Notch1 mRNA expression is significantly increased in basal-like TNBC and strongly correlated with poor survival of patients13. Moreover, specific inhibition of Notch1 signaling has a remarkable inhibitory effect on cancer stem cells and thus increases the sensitivity of TNBC to chemotherapeutic reagents14. Many Notch target molecules have been identified, some of which are particularly important in tumorigenesis, including MYC, IGF1-R, and snail homolog 2 (SLUG)15C17. Survivin, a unique member of the IAP protein family, serves as a dual regulator of cell division and apoptosis18. Mounting evidence has suggested survivin as a pivotal oncoprotein with multiple roles in the regulation of mitosis, suppression of cell death, and enhanced adaptation to cellular stress19. Other evidence also suggests that survivin may be a critical molecule in breast cancer, which links to aggressive disease, resistance to apoptosis, and the modulation of HER2 signaling20. Survivin expression is regulated by several oncogenic pathways, such as Mesna Wnt/-catenin signaling19. Importantly, coexpression of Notch1 and survivin has been found in basal breast cancer21. Stimulation of Notch1 increases the survivin expression in TNBC cells, whereas inhibition of Notch reduces the survivin level, suggesting that survivin is a target of Notch in TNBC. Mesna However, to date, the pathophysiological tasks of Notch-survivin axis in breast cancer progression remain elusive and need to Mesna be further assessed. Mitochondria are highly dynamic IL25 antibody and undergo constant fusion and fission, which is essential for maintaining.
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