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      Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells


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          Pharmacology-based target identification has become a novel strategy leading to the discovery of novel pathological biomarkers. Ellagic acid (EA), a dietary polyphenol compound, exhibits potent anticancer activities; however, the underlying mechanisms remain unclear. The current study sought to determine the role and regulation of ACTN4 expression in human breast cancer metastasis and EA-based therapy.


          The anti-metastasis ability of EA was validated by MMTV-PyMT mice and in vitro cell models. Drug affinity responsive target stability (DARTS) was utilized to identify ACTN4 as the direct target of EA. The metastatic regulated function of ACTN4 were assessed by cancer stem cells (CSCs)-related assays, including mammosphere formation, tumorigenic ability, reattachment differentiation, and signaling pathway analysis. The mechanisms of ACTN4 on β-catenin stabilization were investigated by western blotting, co-immunoprecipitation and ubiquitination assays. The clinical significance of ACTN4 was based on human tissue microarray (TMA) analysis and The Cancer Genome Atlas (TCGA) database exploration.


          EA inhibited breast cancer growth and metastasis via directly targeting ACTN4 in vitro and in vivo, and was accompanied by a limited CSC population. ACTN4 knockdown resulted in the blockage of malignant cell proliferation, colony formation, and ameliorated metastasis potency. ACTN4-positive CSCs exhibited a higher ESA + proportion, increased mammosphere-formation ability, and enhanced in vivo tumorigenesis ability. Mechanism exploration revealed that interruption of ACTN4/β-catenin interaction will result in the activation of β-catenin proteasome degradation. Increased ACTN4 expression was directly associated with the advanced cancer stage, an increased incidence of metastasis, and poor overall survival period.


          Taken together, our results suggest that ACTN4 plays an important role in breast CSCs-related metastasis and is a novel therapeutic target of EA treatment.

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          The online version of this article (10.1186/s13046-017-0635-9) contains supplementary material, which is available to authorized users.

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          Breast cancer metastasis: markers and models.

          Breast cancer starts as a local disease, but it can metastasize to the lymph nodes and distant organs. At primary diagnosis, prognostic markers are used to assess whether the transition to systemic disease is likely to have occurred. The prevailing model of metastasis reflects this view--it suggests that metastatic capacity is a late, acquired event in tumorigenesis. Others have proposed the idea that breast cancer is intrinsically a systemic disease. New molecular technologies, such as DNA microarrays, support the idea that metastatic capacity might be an inherent feature of breast tumours. These data have important implications for prognosis prediction and our understanding of metastasis.
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            Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy

            Introduction The phenotypic and functional differences between cells that initiate human breast tumors (cancer stem cells) and those that comprise the tumor bulk are difficult to study using only primary tumor tissue. We embarked on this study hypothesizing that breast cancer cell lines would contain analogous hierarchical differentiation programs to those found in primary breast tumors. Methods Eight human breast cell lines (human mammary epithelial cells, and MCF10A, MCF7, SUM149, SUM159, SUM1315 and MDA.MB.231 cells) were analyzed using flow cytometry for CD44, CD24, and epithelial-specific antigen (ESA) expression. Limiting dilution orthotopic injections were used to evaluate tumor initiation, while serial colony-forming unit, reconstitution and tumorsphere assays were performed to assess self-renewal and differentiation. Pulse-chase bromodeoxyuridine (5-bromo-2-deoxyuridine [BrdU]) labeling was used to examine cell cycle and label-retention of cancer stem cells. Cells were treated with paclitaxol and 5-fluorouracil to test selective resistance to chemotherapy, and gene expression profile after chemotherapy were examined. Results The percentage of CD44+/CD24- cells within cell lines does not correlate with tumorigenicity, but as few as 100 cells can form tumors when sorted for CD44+/CD24-/low/ESA+. Furthermore, CD44+/CD24-/ESA+ cells can self-renew, reconstitute the parental cell line, retain BrdU label, and preferentially survive chemotherapy. Conclusion These data validate the use of cancer cell lines as models for the development and testing of novel therapeutics aimed at eradicating cancer stem cells.
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              Target identification using drug affinity responsive target stability (DARTS).

              Identifying the molecular targets for the beneficial or detrimental effects of small-molecule drugs is an important and currently unmet challenge. We have developed a method, drug affinity responsive target stability (DARTS), which takes advantage of a reduction in the protease susceptibility of the target protein upon drug binding. DARTS is universally applicable because it requires no modification of the drug and is independent of the mechanism of drug action. We demonstrate use of DARTS to identify known small-molecule-protein interactions and to reveal the eukaryotic translation initiation machinery as a molecular target for the longevity-enhancing plant natural product resveratrol. We envisage that DARTS will also be useful in global mapping of protein-metabolite interaction networks and in label-free screening of unlimited varieties of compounds for development as molecular imaging agents.

                Author and article information

                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                2 December 2017
                2 December 2017
                : 36
                : 172
                [1 ]Department of Breast Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China
                [2 ]ISNI 0000 0000 8848 7685, GRID grid.411866.c, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College & The Research Center of Integrative Medicine, , Guangzhou University of Chinese Medicine, ; Guangzhou Shi, China
                Author information
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                : 10 August 2017
                : 13 November 2017
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81402173, 81573651
                Award Recipient :
                Funded by: Pearl River S&T Nova Program of Guangzhou
                Award ID: 201506010098
                Award Recipient :
                Funded by: Guangdong Science Foundation for Distinguished Young Scholars
                Award ID: 2016A030306025
                Award Recipient :
                Funded by: Combined Scientific Project Funded by Guangdong Provincial Science and Technology Agency and Guangdong Provincial Academy of Traditional Chinese Medicine
                Award ID: 2014A020221047
                Award Recipient :
                Funded by: Guangdong High- level university construction project
                Award ID: A1-AFD018161Z1510
                Award Recipient :
                Funded by: Guangdong High-level Personnel of Special Support Program
                Award ID: A1-3002-16-111-003
                Award Recipient :
                Funded by: International Postdoctoral Exchange Fellowship Program
                Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;
                Award ID: 2016M592585
                Award Recipient :
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy
                cancer stem cells,metastasis,actn4,ellagic acid,β-catenin
                Oncology & Radiotherapy
                cancer stem cells, metastasis, actn4, ellagic acid, β-catenin


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