| Breast cancer is the most common malignant tumor in women world wide. Breast cancers are generally treated with surgery followed by radiotherapy. To avoid recurrence from micrometastases, adjuvant treatments are often prescribed. At present around 40% of breast cancers suffer recurrence and matastasis. BCSCs (Breast cancer stem cells) plays a crucial role in the recurrence, metastasis and resistance to therapy of breast cancers. EMT (Epithelial-mesenchymal transition) is a critical cellular process for controlling the development and progression of breast cancers. It had reported that the EMT generates cells with properties of BCSCs. The purpose of this study is to investigate the mechanisms of BCSCs and EMT for promoting the recurrence and metastasis of breast cancers.Chronic inflammation enhances the development and functions of BCSCs with unclear mechanism. TRB3(Tribbles homolog 3) has been found positively associated with the invasion and metastasis of tumors and the poor prognosis of breast cancers. So we hypothesized that TRB3 regulates chronic inflammation-induced BCSCs formation and maintenance. We found that the expression of TRB3 positively associated with the levels of IL6 and Sox2. The enhanced expression of TRB3 has been found in the IL6-induced CD44+/CD24-populations but not in the CD44-CD24+ populations of MCF-7 cells. Indeed, the overexpression of TRB3 in breast cancer cells, results in increases of the ratio of CD44+/CD24- populations, the ability of mammopheres formation and tumorigenesis in vivo; whereas the depletion of TRB3 in breast cancer cells, reduces the ratio of CD44+/CD24- populations and the ability of mammopheres formation. These data suggest that TRB3 promotes IL6-induced BCSCs formation. We also found that TRB3 ehanced the Sox2 transcription but not influence the Sox2 stability. Through screening a variety of transcription factors, we found that TRB3 promoted the Sox2 transcription in a FoxO1-dependent manner. Indeed, we found that TRB3 repressed the FoxO1 proteasome degradation and increased the FoxO1 transcription in breast cancer cells. Suppression of the interaction between Aktl and FoxO1 by the binding of TRB3 to Aktl resultes in decrease of the expression of p-FoxO1, which is the essential modification of the FoxO1 proteasome degradation. Enhanced FoxO1 expression increased the Sox2 transcription through binding to the Sox2 promoter. Interestingly, we found that Sox2 promoted the FoxO1 transcription by binding to the FoxO1 promoter. Hence, there is a positive crosstalk between Sox2 and FoxO1 in BCSCs. These findings indicate that TRB3 promotes IL6-induced BCSCs formation via suppressing the activity of Aktl-FoxO1 axis and enhancing the activity of the positive crosstalk between Sox2 and FoxO1 in BCSCs. Targeting the interaction between TRB3 and Aktl has therapeutic potential against the development and progression of BCSCs.B-cell CLL/lymphoma 6 (BCL6), a transcriptional repressor, involves in the development and progression of breast cancers with uncertain mechanism. EMT (epithelial-mesenchymal transition) is a critical cellular process for controlling the development and progression of breast cancers. The purpose of this study is to investigate the potential effect and mechanism of BCL6 in the regulation of EMT. We found that BCL6 promoted invasion, migration and growth by stimulating EMT in breast cancer cells. BCL6 induced EMT by enhancing the expression of transcriptional repressor ZEB1 which bound to the E-cadherin promoter and repressing the E-cadherin transcription. Deletion of ZEB1 protected against the pro-EMT roles of BCL6 by restoring the expression of E-cadherin in these cells. Moreover, inhibition of BCL6 with BCL6 inhibitor 79-6 suppressed these functions of BCL6 in breast cancer cells. These findings indicate that BCL6 promotes EMT via enhancing the ZEB1-mediated transcriptional repression of E-cadherin in breast cancer cells. Targeting BCL6 has therapeutic potential against the development and progression of breast cancer. |
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