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ER? inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer.

ABSTRACT: In human breast cancer, estrogen receptor-? (ER?) suppresses epithelial-mesenchymal transition (EMT) and stemness, two crucial parameters for tumor metastasis; however, the underlying mechanism by which ER? regulates these two processes remains largely unknown. Bmi1, the polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog, regulates EMT transition, maintains the self-renewal capacity of stem cells, and is frequently overexpressed in human cancers. In the present study, ER? upregulated the expression of the epithelial marker, E-cadherin, in breast cancer cells through the transcriptional down-regulation of Bmi1. Furthermore, ER? overexpression suppressed the migration, invasion, and EMT of breast cancer cells. Notably, overexpression of ER? significantly decreased the CD44high/CD24low cell population and inhibited the capacity for mammosphere formation in ER?-negative breast cancer cells. In addition, overexpression of Bmi1 attenuated the ER?-mediated suppression of EMT and cell stemness. Immunohistochemistry revealed an inverse association of ER? and Bmi1 expression in human breast cancer tissue. Taken together, our findings suggest that ER? inhibits EMT and stemness through the downregulation of Bmi1.

SUBMITTER: Wei XL

PROVIDER: S-EPMC4673297 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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ERα inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer.

Wei Xiao-Long XL Dou Xiao-Wei XW Bai Jing-Wen JW Luo Xiang-Rong XR Qiu Si-Qi SQ Xi Di-Di DD Huang Wen-He WH Du Cai-Wen CW Man Kwan K Zhang Guo-Jun GJ

Oncotarget 20150801 25

In human breast cancer, estrogen receptor-α (ERα) suppresses epithelial-mesenchymal transition (EMT) and stemness, two crucial parameters for tumor metastasis; however, the underlying mechanism by which ERα regulates these two processes remains largely unknown. Bmi1, the polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog, regulates EMT transition, maintains the self-renewal capacity of stem cells, and is frequently overexpressed in human cancers. In the present study, ERα upregu ...[more]

PMID: 26023734

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Project description: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 NF?B promoter activity. RT-PCR analysis showed that Bmi1 overexpression activated the NF?B pathway whereas Bmi1 knockdown reduced the expression of NF?B target genes, suggesting that Bmi1 might regulate Nanog expression through the NF?B 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 NF?B pathway.

Project description:Our previous studies demonstrated that the natural compound emodin blocks the tumor-promoting feedforward interactions between cancer cells and macrophages, and thus ameliorates the immunosuppressive state of the tumor microenvironment. Since tumor-associated macrophages (TAMs) also affect epithelial mesenchymal-transition (EMT) and cancer stem cell (CSC) formation, here we aimed to test if emodin as a neoadjuvant therapy halts breast cancer metastasis by attenuating TAM-induced EMT and CSC formation of breast cancer cells. Methods: Bioinformatical analysis was performed to examine the correlation between macrophage abundance and EMT/CSC markers in human breast tumors. Cell culture and co-culture studies were performed to test if emodin suppresses TGF-?1 or macrophage-induced EMT and CSC formation of breast cancer cells, and if it inhibits breast cancer cell migration and invasion. Using mouse models, we tested if short-term administration of emodin before surgical removal of breast tumors halts breast cancer post-surgery metastatic recurrence in the lungs. The effects of emodin on TGF-?1 signaling pathways in breast cancer cells were examined by western blots and immunofluorescent imaging. Results: Macrophage abundance positively correlates with EMT and CSC markers in human breast tumors. Emodin suppressed TGF-?1 production in breast cancer cells and macrophages and attenuated TGF-?1 or macrophage-induced EMT and CSC formation of breast cancer cells. Short-term administration of emodin before surgery halted breast cancer post-surgery metastatic recurrence in the lungs by reducing tumor-promoting macrophages and suppressing EMT and CSC formation in the primary tumors. Mechanistic studies revealed that emodin inhibited both canonical and noncanonical TGF-?1 signaling pathways in breast cancer cells and suppressed transcription factors key to EMT and CSC. Conclusion: Natural compound emodin suppresses EMT and CSC formation of breast cancer cells by blocking TGF-?1-mediated crosstalk between TAMs and breast cancer cells. Our study provides evidence suggesting that emodin harbors the potential for clinical development as a new effective and safe agent to halt metastatic recurrence of breast cancer.

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ER? inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer.

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ERα inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer.

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