Effects Of Notch Pathway On Regulating Breast Cancer Stem Cells (BCSCs) And Purifying BCSCs In Triple-negative Breast Cancer

In recent years,the incidence and prognosis of breast cancer is not optimistic.Clinical and scientific researchers keep close attention to these issues and strive to find appropriate treatment strategies for breast cancer patients.Radiotherapy,chemotherapy or hormone therapy combined with surgical excision is the current common strategy for the treatment of breast cancer.The application of these treatments in the clinic shows the effect of prolonging the survival time of patients.But during the course of treatment,tumor recurrence and metastasis often occur.In the process of exploring these phenomena,the "cancer stem cell" hypothesis was put forward and used to explain this phenomenon.Tumor stem cells have the characteristics of self-renewal,differentiation and strong drug resistance.These characteristics enable cancer stem cells to survive in the treatment process and proliferate and differentiate in a certain period of time,leading to tumor recurrence and metastasis.Therefore,how to effectively inhibit or eradicate cancer stem cells will be the goal of developing new strategies for the treatment of breast cancer.In view of the fact that many signaling pathways regulate the differentiation and proliferation of cancer stem cells,the key factors targeting these signaling pathways have become an important research direction in the treatment of cancer stem cells.Inhibitors of Notch signaling pathway have been used in clinical trials.However,clinical results show that these inhibitors are not as effective as expected.The main contents were as follows:1,Notch pathways play important roles in carcinogenesis including pathways involving the Notch1 and Notch2 oncogenes.Pan-Notch inhibitors,such as gamma secretase inhibitors(GSIs),have been used in the clinical trials,but the outcomes of these trials have been insufficient.In the present study,we demonstrated that GSIs,such as MK-0752 and RO4929097,inhibit breast tumor growth,but increase the breast cancer stem cell population in Notch3-expressing breast cancer cells,in a process that is coupled with IL6 induction and is blocked by the IL6R antagonist Tocilizumab(TCZ).IL6 induction results from inhibition of Notch3-Hey2 signaling through MK-0752.Furthermore,HIF1α upregulates Notch3 expression via direct binding to the Notch3 promoter and subsequently downregulates BCSCs by decreasing the IL6 level in Notch3-expressing breast cancer cells.Utilizing both breast cancer cell line xenografts and patient-derived xenografts,we showed that the combination of MK-0752 and IL6R blocking antibody Tocilizumab significantly decreases BCSCs and inhibits tumor growth and thus might serve as a novel therapeutic strategy for treating women with Notch3-expressing breast cancers.2,In breast cancer,ALDH(Aldehyde dehydrogenase)and CD24-CD44+ have been used as breast cancer stem cell(BCSC)markers,which enriched BCSCs but can not serve as pure BCSC markers.Especially in triple negative breast cancer,it has a large population of CD24-CD44+,therefore,CD24-CD44+ is not suitable for use as a marker.New and specific markers need to be discovered.In this study,we found that tumor cells labeled as Notch4+CD24-CD44+ have the strongest tumorigenic ability by in vivo tumor formation experiments,which confirmed that Notch4 combined with CD24-CD44+ may mark BCSCs more specifically.Further experiments to define the mechanisms are under way.