Short-Form Ron Promotes Spontaneous Breast Cancer Metastasis through Interaction with Phosphoinositide 3-Kinase

Xuemei Liu, Ling Zhao, Yoko S. DeRose, Yi Chun Lin, Magdalena Bieniasz, Henok Eyob, Saundra S. Buys, Leigh Neumayer, Alana L. Welm

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Receptor tyrosine kinases (RTKs) have been the subject of intense investigation due to their widespread deregulation in cancer and the prospect of developing targeted therapeutics against these proteins. The Ron RTK has been implicated in tumor aggressiveness and is a developing target for therapy, but its function in tumor progression and metastasis is not fully understood. We examined Ron activity in human breast cancers and found striking predominance of an activated Ron isoform known as short-form Ron (sfRon), whose function in breast tumors has not been explored. We found that sfRon plays a significant role in aggressiveness of breast cancer in vitro and in vivo. sfRon expression was sufficient to convert slow-growing, nonmetastatic tumors into rapidly growing tumors that spontaneously metastasized to liver and bones. Mechanistic studies revealed that sfRon promotes epithelial-mesenchymal transition, invasion, tumor growth, and metastasis through interaction with p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K activity, or introduction of a single mutation in the p85 docking site on sfRon, completely eliminated the ability of sfRon to promote tumor growth, invasion, and metastasis. These findings reveal sfRon as an important new player in breast cancer and validate Ron and PI3K as therapeutic targets in this disease.

Original languageEnglish (US)
Pages (from-to)753-762
Number of pages10
JournalGenes and Cancer
Volume2
Issue number7
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

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Keywords

  • PI3K
  • Ron
  • breast cancer
  • metastasis
  • short-form Ron

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Liu, X., Zhao, L., DeRose, Y. S., Lin, Y. C., Bieniasz, M., Eyob, H., Buys, S. S., Neumayer, L., & Welm, A. L. (2011). Short-Form Ron Promotes Spontaneous Breast Cancer Metastasis through Interaction with Phosphoinositide 3-Kinase. Genes and Cancer, 2(7), 753-762. https://doi.org/10.1177/1947601911421924