The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers

Kwai Wa Cheng, John P. Lahad, Wen Lin Kuo, Anna Lapuk, Kyosuke Yamada, Nelly Auersperg, Jinsong Liu, Karen Smith-McCune, Karen H. Lu, David Fishman, Joe W. Gray, Gordon B. Mills

Research output: Contribution to journalArticlepeer-review

384 Scopus citations

Abstract

High-density array comparative genomic hybridization (CGH) showed amplification of chromosome 1q22 centered on the RAB25 small GTPase, which is implicated in apical vesicle trafficking, in approximately half of ovarian and breast cancers. RAB25 mRNA levels were selectively increased in stage III and IV serous epithelial ovarian cancers compared to other genes within the amplified region, implicating RAB25 as a driving event in the development of the amplicon. Increased DNA copy number or RNA level of RAB25 was associated with markedly decreased disease-free survival or overall survival in ovarian and breast cancers, respectively. Forced expression of RAB25 markedly increased anchorage-dependent and anchorage-independent cell proliferation, prevented apoptosis and anoikis, including that induced by chemotherapy, and increased aggressiveness of cancer cells in vivo. The inhibition of apoptosis was associated with a decrease in expression of the proapoptotic molecules, BAK and BAX, and activation of the antiapoptotic phosphatidylinositol 3 kinase (PI3K) and AKT pathway, providing potential mechanisms for the effects of RAB25 on tumor aggressiveness. Overall, these studies implicate RAB25, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers.

Original languageEnglish (US)
Pages (from-to)1251-1256
Number of pages6
JournalNature medicine
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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