Abstract
The polycomb group transcriptional modifier Bmi1 is often upregulated in numerous cancers and is intensely involved in normal and cancer stem cells, and importantly is as a prognostic indicator for some cancers, but its role in breast cancer remains unclear. Here, we found Bmi1 overexpression in 5-Fu (5-fluorouracil)-resistant MCF-7 cells (MCF-7/5-Fu) derived from MCF-7 breast cancer cells, MDA-MB-231 and MDA-MB-453 breast cancer cells compared to MCF-7 cells, was related with 5-Fu resistance and enrichment of CD44+/CD24- stem cell subpopulation. Bmi1 knockdown enhanced the sensitivity of breast cancer cells to 5-Fu and 5-Fu induced apoptosis via mitochondrial apoptotic pathway, and decreased the fraction of CD44+/CD24- subpopulation. In addition, our analysis showed inverse expression pattern between Bmi1 and miR-200c and miR-203 in selected breast cancer cell lines, and miR-200c and miR-203 directly repressed Bmi1 expression in protein level confirmed by luciferase reporter assay. MiR-200c and miR-203 overexpression in breast cancer cells downregulated Bmi1 expression accompanied with reversion of resistance to 5-Fu mediated by Bmi1. Inversely, Bmi1 overexpression inhibited miR-200c expression in MCF-7 cells, but not miR-203, however ectopic wild-type p53 expression reversed Bmi1 mediated miR-200c downregulation, suggesting the repressive effect of Bmi1 on miR-200c maybe depend on p53. Thus, our study suggests a cross-talk between Bmi1 and miR-200c mediated by p53, and Bmi1 interference would improve chemotherapy efficiency in breast cancer via susceptive apoptosis induction and cancer stem cell enrichment inhibition.
Highlights
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide, accounting for 23% (1.38 million) of the total new cancer cases and 14% (458,400) of the total cancer deaths in 2008 [1]
Bmi1 contributes to resistance to 5-Fu and BCSCs traits maintain in breast cancer cells
We found ectopic expression of Bmi1 enhanced MCF-7 resistant to 5-Fu, and Bmi1 knockdown with short hairpin RNAs (shRNA) sensitized MCF-7/5-Fu, MDA-MB-231 and MDA-MB-453 cells to 5-Fu (Figure 1D)
Summary
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide, accounting for 23% (1.38 million) of the total new cancer cases and 14% (458,400) of the total cancer deaths in 2008 [1]. The majority of cancer patients, even if they show an initial response to chemotherapy drugs, will develop aggressive malignancies including metastasis and relapse, which exhibit up to 90% resistance to one or more drugs [4,5]. This intensely suggests that drug resistance, whether intrinsic or acquired over time, constitutes a major hurdle to successful breast cancer treatment, leading to ultimate cancer death. It has been suggested that a small subpopulation of cells within tumors, termed as “tumor-initiating cells” (TICs) or “cancer stem cells” (CSCs), may be resistant to chemotherapy and may reinitiate tumor growth after treatment [8]. Full understanding on CSCs may offer promise for eliciting the mechanisms of intrinsic or acquired resistance, and may reveal the molecular targets for revising the resistance
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