Bmi-1 induces radioresistance in MCF-7 mammary carcinoma cells

Liu, Zhi Gang; Liu, Li; Xu, Li; Yi, Wei; Tao, Yuan; Tu, Zi Wei; Li, Man Zhi; Zeng, Mu Sheng; Xia, Yun

doi:10.3892/or.2011.1615

Cited by 34 publications

(27 citation statements)

References 39 publications

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“…Few studies have associated Bmi1 with radio-resistance and drug-resistance in breast cancer cells [43, 44]. To study the effect of Bmi1 knockdown on drug response of NBLE-LP and MDAMB231 cells we treated vector control and shBmi1 cells with anti-cancer drug doxorubicin for 48 hrs.…”

Section: Resultsmentioning

confidence: 99%

Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog

et al. 2014

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BackgroundThe Bmi1 polycomb ring finger oncogene, a transcriptional repressor belonging to the Polycomb group of proteins plays an important role in the regulation of stem cell self-renewal and is elevated in several cancers. In the current study, we have explored the role of Bmi1 in regulating the stemness and drug resistance of breast cancer cells.MethodsUsing real time PCR and immunohistochemistry primary breast tissues were analyzed. Retro- and lentiviruses were utilized to overexpress and knockdown Bmi1, RT-PCR and Western blot was performed to evaluate mRNA and protein expression. Stemness properties were analyzed by flow cytometry and sphere-formation and tumor formation was determined by mouse xenograft experiments. Dual luciferase assay was employed to assess promoter activity and MTT assay was used to analyze drug response.ResultsWe found Bmi1 overexpression in 64% of grade III invasive ductal breast adenocarcinomas compared to normal breast tissues. Bmi1 overexpression in immortalized and transformed breast epithelial cells increased their sphere-forming efficiency, induced epithelial to mesenchymal transition (EMT) with an increase in the expression of stemness-related genes. Knockdown of Bmi1 in tumorigenic breast cells induced epithelial morphology, reduced expression of stemness-related genes, decreased the IC50 values of doxorubicin and abrogated tumor-formation. Bmi1-high tumors showed elevated Nanog expression whereas the tumors with lower Bmi1 showed reduced Nanog levels. Overexpression of Bmi1 increased Nanog levels whereas knockdown of Bmi1 reduced its expression. Dual luciferase promoter-reporter assay revealed Bmi1 positively regulated the Nanog and NFκB promoter activity. RT-PCR analysis showed that Bmi1 overexpression activated the NFκB pathway whereas Bmi1 knockdown reduced the expression of NFκB target genes, suggesting that Bmi1 might regulate Nanog expression through the NFκB pathway.ConclusionsOur study showed that Bmi1 is overexpressed in several high-grade, invasive ductal breast adenocarcinomas, thus supporting its role as a prognostic marker. While Bmi1 overexpression increased self-renewal and promoted EMT, its knockdown reversed EMT, reduced stemness, and rendered cells drug sensitive, thus highlighting a crucial role for Bmi1 in regulating the stemness and drug response of breast cancer cells. Bmi1 may control self-renewal through the regulation of Nanog expression via the NFκB pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-785) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog

et al. 2014

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“…Bmi-1 has been demonstrated to be overexpressed in various of tumors (8), such as lung (9), breast (10) and prostate cancer (11), esophageal carcinoma (12) and NPC (13). Bmi-1 inhibition has been shown to sensitize those tumor cells to radiation (10,14,15). However, whether Bmi-1 inhibition can potentiate the cytotoxic effects of radiation on nasopharyngeal CSCs remains to be elucidated.…”

Section: Introductionmentioning

confidence: 97%

“…B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), a member of the Polycomb family of transcriptional repressors, is essential for maintaining the self-renewal and differentiation of human stem cells (4)(5)(6)(7). Bmi-1 has been demonstrated to be overexpressed in various of tumors (8), such as lung (9), breast (10) and prostate cancer (11), esophageal carcinoma (12) and NPC (13). Bmi-1 inhibition has been shown to sensitize those tumor cells to radiation (10,14,15).…”

Section: Introductionmentioning

confidence: 99%

shRNA targeting Bmi-1 sensitizes CD44+ nasopharyngeal cancer stem-like cells to radiotherapy

Liu

et al. 2014

Oncology Reports

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Accumulating evidence indicates that cancer stem cells (CSCs) are involved in resistance to radiation therapy (RT). Bmi-1, a member of the Polycomb family of transcriptional repressors, is essential for maintaining the self-renewal abilities of stem cells and overexpression of Bmi-1 correlates with cancer therapy failure. Our previous study identified that the CD44+ nasopharyngeal cancer (NPC) cells may be assumed as one of markers of nasopharyngeal carcinoma cancer stem cell-like cells (CSC-LCs) and Bmi-1 is overexpressed in CD44+ NPC. In the present study, we used RNA interference technology to knock down the expression of Bmi-1 in CD44+ NPC cells, and then measured the radiation response by clonogenic cell survival assay. DNA repair was monitored by γH2AX foci formation. Bmi-1 downstream relative gene and protein expression of p16, p14, p53 were assessed by western blotting and real-time PCR. Cell cycle and apoptosis were detected by flow cytometry assays. We found that Bmi-1 knockdown prolonged G1 and enhanced the radiation-induced G2/M arrest, inhibited DNA damage repair, elevated protein p16, p14 and p53 expression, leading to increased apoptosis in the radiated CD44+ cells. These data suggest that Bmi-1 downregulation increases the radiosensitivity to CD44+ NPC CSC-LCs. Bmi-1 is a potential target for increasing the sensitivity of NPC CSCs to radiotherapy.

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“…It is regulated by complex interactions between anti-apoptotic proteins such as Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic proteins including Bax, Bak, Bad and Bim [8,9]. Down regulation of anti-apoptotic proteins can promote apoptosis and enhance the radiosensitivity of cancer cells [10-13]. The disruption of anti-apoptotic pathways is a novel target for overcoming radioresistance in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL

Jin

et al. 2012

J Exp Clin Cancer Res

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BackgroundAcquired radioresistance of cancer cells remains a fundamental barrier to attaining the maximal efficacy of radiotherapy for the treatment of breast cancer. Anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, play an important role in the radioresistance of cancer cells. In the present study, we aimed to determine if ABT-737, a BH3-only mimic, could reverse the acquired radioresistance of the breast cancer cell line MDA-MB-231R by targeting Bcl-2 and Bcl-xL.MethodsThe radiosensitivity of MDA-MB-231 and MDA-MB-231R cells was compared using colony formation assays. Reverse-transcription PCR and western blot were performed to detect the expression of Bcl-2 and Bcl-xL in the cancer cell lines. Annexin V flow cytometric analysis and caspase-3 colorimetric assay were used to evaluate apoptosis of the cancer cells. Cell viability was measured using the Cell Counting Kit-8. The animals used in this study were 4 to 6-week-old athymic female BALB/c nu/nu mice.ResultsThe MDA-MB-231R cells were more radioresistant than the MDA-MB-231 cells, and Bcl-2 and Bcl-xL were overexpressed in the MDA-MB-231R cells. While ABT-737 was able to restore the radiosensitivity of the MDA-MB-231R cells in vitro and in vivo experiment, it was not able to enhance the radiosensitivity of the MDA-MB-231 cells. In addition, ABT-737 increased radiation-induced apoptosis in the MDA-MB-231R cells. Bcl-2 and Bcl-xL were down regulated in the MDA-MB-231R cells following treatment with ABT-737.ConclusionsTargeting of the anti-apoptotic proteins Bcl-2 and Bcl-xL with ABT-737 may reverse the acquired radioresistance of MDA-MB-231R cells in vitro and in vivo. These findings suggest an attractive strategy for overcoming the acquired radioresistance of breast cancer cells.

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Bmi-1 induces radioresistance in MCF-7 mammary carcinoma cells

Cited by 34 publications

References 39 publications

Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog

Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog

shRNA targeting Bmi-1 sensitizes CD44+ nasopharyngeal cancer stem-like cells to radiotherapy

ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL

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