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. Cancer Discov; 4(3); 1–14. ©2014 AACR.
See related commentary by Ferrer and Reginato, p. xxx.
Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).
- Received June 14, 2013.
- Revision received December 9, 2013.
- Accepted December 23, 2013.
- ©2014 American Association for Cancer Research.