title: An in vivo functional screen identifies ST6GalNAc2 sialyltransferase as a breast cancer metastasis suppressor.
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.
authors: 1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research; 2Cardiovascular Division, King's College London, British Heart Foundation Centre for Research Excellence, James Black Centre; and 3Division of Molecular Biosciences, Imperial College London, London, United Kingdom.
authors: Nirupa
authors: N
authors: Murugaesu
authors: Marjan
authors: M
authors: Iravani
authors: Antoinette
authors: A
authors: van Weverwijk
authors: Aleksandar
authors: A
authors: Ivetic
authors: Damian A
authors: DA
authors: Johnson
authors: Aristotelis
authors: A
authors: Antonopoulos
authors: Antony
authors: A
authors: Fearns
authors: Mariam
authors: M
authors: Jamal-Hanjani
authors: David
authors: D
authors: Sims
authors: Kerry
authors: K
authors: Fenwick
authors: Costas
authors: C
authors: Mitsopoulos
authors: Qiong
authors: Q
authors: Gao
authors: Nick
authors: N
authors: Orr
authors: Marketa
authors: M
authors: Zvelebil
authors: Stuart M
authors: SM
authors: Haslam
authors: Anne
authors: A
authors: Dell
authors: Helen
authors: H
authors: Yarwood
authors: Christopher J
authors: CJ
authors: Lord
authors: Alan
authors: A
authors: Ashworth
authors: Clare M
authors: CM
authors: Isacke
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D005260:Female; D037502:Galectin 3 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: D037502:Galectin 3; D012799:Sialyltransferases; C088391:galactosyl-1-3-N-acetylgalactosaminyl-specific 2,6-sialyltransferase