期刊
CANCER DISCOVERY
卷 4, 期 3, 页码 304-317出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0287
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资金
- Breakthrough Breast Cancer
- Biotechnology and Biological Sciences Research Council [BBF008309, BBK016164]
- British Heart Foundation Centre of Research Excellence at King's College London
- BBSRC [BB/F008309/1, BB/K016164/1] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL7-Murugaesu] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/F008309/1, BB/K016164/1] Funding Source: researchfish
- National Institute for Health Research [CL-2011-18-001] Funding Source: researchfish
To interrogate the complex mechanisms involved in the later stages of cancer metastasis, we designed a functional in vivo RNA interference (RNAi) screen combined with next-generation sequencing. Using this approach, we identified the sialyltransferase ST6GalNAc2 as a novel breast cancer metastasis suppressor. Mechanistically, ST6GalNAc2 silencing alters the profile of O-glycans on the tumor cell surface, facilitating binding of the soluble lectin galectin-3. This then enhances tumor cell retention and emboli formation at metastatic sites leading to increased metastatic burden, events that can be completely blocked by galectin-3 inhibition. Critically, elevated ST6GALNAC2, but not galectin-3, expression in estrogen receptor-negative breast cancers significantly correlates with reduced frequency of metastatic events and improved survival. These data demonstrate that the prometastatic role of galectin-3 is regulated by its ability to bind to the tumor cell surface and highlight the potential of monitoring ST6GalNAc2 expression to stratify patients with breast cancer for treatment with galectin-3 inhibitors. SIGNIFICANCE: RNAi screens have the potential to uncover novel mechanisms in metastasis but do not necessarily identify clinically relevant therapeutic targets. Our demonstration that the sialyltransferase ST6GalNAc2 acts as a metastasis suppressor by impairing binding of galectin-3 to the tumor cell surface offers the opportunity to identify patients with breast cancer suitable for treatment with clinically well-tolerated galectin-3 inhibitors. (C) 2014 AACR.
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