CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling

被引：93
作者：
Dubrovska, A. [1 ]
Hartung, A. [2 ]
Bouchez, L. C. [1 ]
Walker, J. R. [2 ]
Reddy, V. A. [2 ]
Cho, C. Y. [2 ]
Schultz, P. G. [1 ]
机构：
[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[2] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
来源：
BRITISH JOURNAL OF CANCER | 2012年 / 107卷 / 01期
关键词：
tamoxifen resistance; cancer progenitors; CXCR4; AhR; ARYL-HYDROCARBON RECEPTOR; ABC TRANSPORTERS; PATHWAY; METASTASIS; EXPRESSION; GROWTH; GENE; THERAPY; 17-BETA-ESTRADIOL; ANTIESTROGENS;
D O I：
10.1038/bjc.2012.105
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
BACKGROUND: Tamoxifen is commonly used for breast cancer therapy. However, tamoxifen resistance is an important clinical problem. Continuous treatment with conventional therapy may contribute to cancer progression in recurring cancers through the accumulation of drug-resistant cancer progenitors. METHODS: To investigate signalling mechanisms important for the maintenance and viability of drug-resistant cancer progenitors, we used microarray analysis, PCR array for genes involved in cancer drug resistance and metabolism, flow cytometry, soft agar colony formation assay, in vivo tumourigenicity assay and immunohistochemical analysis using tamoxifen-sensitive and tamoxifen-resistant breast cancer MCF7 cells. RESULTS: Downregulation of CXCR4 signalling by small molecule antagonist AMD3100 specifically inhibits growth of progenitor cell population in MCF7(TAM-R) cells both in vitro and in vivo. Microarray analysis revealed aryl hydrocarbon receptor (AhR) signalling as one of the top networks that is differentially regulated in MCF7(TAM-R) and MCF7 xenograft tumours treated with AMD3100. Further, small molecule antagonists of AhR signalling specifically inhibit the progenitor population in MCF7(TAM-R) cells and growth of MCF7(TAM-R) xenografts in vivo. CONCLUSION: The chemokine receptor CXCR4 maintains a cancer progenitor population in tamoxifen-resistant MCF7 cells through AhR signalling and could be a putative target for the treatment of tamoxifen-resistant breast cancers. British Journal of Cancer (2012) 107, 43-52. doi:10.1038/bjc.2012.105 www.bjcancer.com Published online 29 May 2012 (C) 2012 Cancer Research UK
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页码：43 / 52
页数：10
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