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 Gray, Gordon Mills

Research output: Contribution to journalArticle

372 Citations (Scopus)

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 2004
Externally publishedYes

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Monomeric GTP-Binding Proteins
Ovarian Neoplasms
Phosphatidylinositol 3-Kinase
Apoptosis
Breast Neoplasms
Chemotherapy
Cell proliferation
Chromosomes
Anoikis
Amplification
Tumors
Neoplasms
Comparative Genomic Hybridization
Genes
Chemical activation
Cells
RNA
Messenger RNA
Molecules
Disease-Free Survival

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cheng, K. W., Lahad, J. P., Kuo, W. L., Lapuk, A., Yamada, K., Auersperg, N., ... Mills, G. (2004). The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nature Medicine, 10(11), 1251-1256. https://doi.org/10.1038/nm1125

The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. / Cheng, Kwai Wa; Lahad, John P.; Kuo, Wen Lin; Lapuk, Anna; Yamada, Kyosuke; Auersperg, Nelly; Liu, Jinsong; Smith-McCune, Karen; Lu, Karen H.; Fishman, David; Gray, Joe; Mills, Gordon.

In: Nature Medicine, Vol. 10, No. 11, 11.2004, p. 1251-1256.

Research output: Contribution to journalArticle

Cheng, KW, Lahad, JP, Kuo, WL, Lapuk, A, Yamada, K, Auersperg, N, Liu, J, Smith-McCune, K, Lu, KH, Fishman, D, Gray, J & Mills, G 2004, 'The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers', Nature Medicine, vol. 10, no. 11, pp. 1251-1256. https://doi.org/10.1038/nm1125
Cheng KW, Lahad JP, Kuo WL, Lapuk A, Yamada K, Auersperg N et al. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nature Medicine. 2004 Nov;10(11):1251-1256. https://doi.org/10.1038/nm1125
Cheng, Kwai Wa ; Lahad, John P. ; Kuo, Wen Lin ; Lapuk, Anna ; Yamada, Kyosuke ; Auersperg, Nelly ; Liu, Jinsong ; Smith-McCune, Karen ; Lu, Karen H. ; Fishman, David ; Gray, Joe ; Mills, Gordon. / The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. In: Nature Medicine. 2004 ; Vol. 10, No. 11. pp. 1251-1256.
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