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.
Highlights
When breast carcinomas remain confined to breast tissue, cure rates exceed 90%
Cell-based RNA interference (RNAi) screens have been highly informative in identifying genes involved in tumor cell survival, migration, and invasion [4, 7,8,9], these in vitro approaches are largely unsuitable for interrogating the later stages of the metastatic process, in particular tumor cell dissemination, tumor cell extravasation from the circulation, and colonization of secondary sites
Screen to identify novel determinants of the metastatic process in solid tumors [5]. In contrast to this published study, which used a zero-event model, we have developed an in vivo metastasis short hairpin RNAi screen combined with massive parallel sequencing to identify enrichment of novel determinants involved in the later stages of breast cancer metastasis
Summary
When breast carcinomas remain confined to breast tissue, cure rates exceed 90% (http://seer.cancer.gov/csr/1975_2006/). There is an urgent need to identify genes that control the different stages of the metastatic process in order to aid in the development of metastatic biomarkers and provide potential targets for the treatment and prevention of metastatic disease [2]. Genetic screens, such as those that exploit RNA interference (RNAi), provide an unbiased approach to the identification of genes associated with a phenotype of interest [3,4,5,6]. More recent RNAi screens performed in animal models have provided important new insights into in vivo tumor biology [3,4,5,6]; there has, to date, been only one published in vivo RNAi
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