Total flavonoids of Litchi seed attenuate stem cell-like properties in breast cancer by regulating Notch3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Breast cancer has been the most commonly-diagnosed cancer worldwide, and the treatment and prognosis of which are often limited by breast cancer stem cells (BCSCs). Litchi seeds have shown good anti-cancer activity in various cancers including prostate cancer, lung cancer and breast cancer. However, the activity and underlying mechanism of Litchi seeds against BCSCs remain unknown. AIM OF THE STUDY: To investigate the activity and mechanism of total flavonoids of litchi seed (TFLS) against BCSCs in vitro and in vivo. MATERIALS AND METHODS: Two orthotopic xenograft mouse models were established using HCC1806 cells pretreated or untreated with TFLS to determine whether TFLS could target BCSCs in vivo. Mammosphere formation and flow cytometry assays were employed to evaluate the effect of TFLS on BCSCs in vitro. The underlying mechanism was investigated using RT-qPCR, Western blot, immunohistochemistry and immunofluorescence experiments. RESULTS: TFLS could significantly inhibit the viability of HCC1806, MCF-7 and HCC1937 cells in vitro and suppress the growth of HCC1806 cells in vivo. TFLS attenuated stem cell-like properties of breast cancer through reducing the percentage of CD44+CD24-/low cells, inhibiting the mammospheres formation and down-regulating the mRNA and protein levels of cancer stem cells related markers (Oct4, Nanog, Sox2) in MCF-7 and HCC1806 cells. Meanwhile, TFLS suppressed the tumor-initiating ability of BCSCs via reducing the percentage of CD44+CD24-/low cells in tumor and lowering tumor incidence rate in orthotopic xenograft mice. In addition, TFLS treatments restricted the expression and nuclear translocation of Notch3, subsequently down-regulated Hes1 and Runx2 expressions. CONCLUSIONS: TFLS could suppress the growth of breast cancer and eliminate breast cancer stem cells by inhibiting the Notch3 signaling pathway.

Establishment and Analysis of an Individualized EMT-Related Gene Signature for the Prognosis of Breast Cancer in Female Patients.

Background: The current high mortality rate of female breast cancer (BC) patients emphasizes the necessity of identifying powerful and reliable prognostic signatures in BC patients. Epithelial-mesenchymal transition (EMT) was reported to be associated with the development of BC. The purpose of this study was to identify prognostic biomarkers that predict overall survival (OS) in female BC patients by integrating data from TCGA database. Method: We first downloaded the dataset in TCGA and identified gene signatures by overlapping candidate genes. Differential analysis was performed to find differential EMT-related genes. Univariate regression analysis was then performed to identify candidate prognostic variables. We then developed a prognostic model by multivariate analysis to predict OS. Calibration curves, receiver operating characteristics (ROC) curves, C-index, and decision curve analysis (DCA) were used to test the veracity of the prognostic model. Result: In this study, we identified and validated a prognostic model integrating age and six genes (CD44, P3H1, SDC1, COL4A1, TGFß1, and SERPINE1). C-index values for BC patients were 0.672 (95% CI 0.611-0.732) and 0.692 (95% CI 0.586-0.798) in the training cohort and test set, respectively. The calibration curve and the DCA curve show the good predictive performance of the model. Conclusion: This study offered a robust predictive model for OS prediction in female BC patients and may provide a more accurate treatment strategy and personalized therapy in the future.