An in vivo functional screen identifies ST6GalNAc2 sialyltransferase as a breast cancer metastasis suppressor

Nirupa Murugaesu, Marjan Iravani, Antoinette van Weverwijk, Aleksandar Ivetic, Damian A Johnson, Aristotelis Antonopoulos, Antony Fearns, Mariam Jamal-Hanjani, David Sims, Kerry Fenwick, Costas Mitsopoulos, Qiong Gao, Nick Orr, Marketa Zvelebil, Stuart M Haslam, Anne Dell, Helen Yarwood, Christopher J Lord, Alan Ashworth, Clare M Isacke

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46 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)304-317
Number of pages14
JournalCancer discovery
Volume4
Issue number3
DOIs
Publication statusPublished - Mar 2014

Keywords

  • Animals
  • Breast Neoplasms
  • Cell Line
  • Female
  • Galectin 3
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lung Neoplasms
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Inbred BALB C
  • RNA Interference
  • Sialyltransferases
  • Journal Article
  • Research Support, Non-U.S. Gov't

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  • Cite this

    Murugaesu, N., Iravani, M., van Weverwijk, A., Ivetic, A., Johnson, D. A., Antonopoulos, A., Fearns, A., Jamal-Hanjani, M., Sims, D., Fenwick, K., Mitsopoulos, C., Gao, Q., Orr, N., Zvelebil, M., Haslam, S. M., Dell, A., Yarwood, H., Lord, C. J., Ashworth, A., & Isacke, C. M. (2014). An in vivo functional screen identifies ST6GalNAc2 sialyltransferase as a breast cancer metastasis suppressor. Cancer discovery, 4(3), 304-317. https://doi.org/10.1158/2159-8290.CD-13-0287