The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers.

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.
Authors	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
Journal	Nature medicine (Nat Med) Vol. 10 Issue 11 Pg. 1251-6 (Nov 2004) ISSN: 1078-8956 [Print] United States
PMID	15502842 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	BAK1 protein, human BAX protein, human Bak1 protein, mouse Bax protein, mouse Membrane Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 RNA, Messenger bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt rab GTP-Binding Proteins
Topics	Animals Apoptosis (genetics) Breast Neoplasms (genetics) Cell Proliferation Chromosomes, Human, Pair 1 (genetics) Female Gene Expression Regulation Humans Immunoblotting Membrane Proteins (metabolism) Mice Mice, Inbred BALB C Nucleic Acid Hybridization (methods) Ovarian Neoplasms (genetics) Phosphatidylinositol 3-Kinases (metabolism) Protein Serine-Threonine Kinases (metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 (metabolism) RNA Interference RNA, Messenger (genetics, metabolism) Reverse Transcriptase Polymerase Chain Reaction Transfection Tumor Cells, Cultured bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein rab GTP-Binding Proteins (genetics, metabolism)

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