Data from An <i>In Vivo</i> Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor

Abstract

<div>Abstract<p>To interrogate the complex mechanisms involved in the later stages of cancer metastasis, we designed a functional <i>in vivo</i> 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 <i>O</i>-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 <i>ST6GALNAC2</i>, 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.</p><p><b>Significance:</b> 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. <i>Cancer Discov; 4(3); 304–17. ©2014 AACR.</i></p><p>See related commentary by Ferrer and Reginato, p. 275</p><p>This article is highlighted in the In This Issue feature, p. 259</p></div>