Nature Medicine
10, 1251 - 1256 (2004)
Published online: 24 October 2004; | doi:10.1038/nm1125
The RAB25 small GTPase determines aggressiveness of ovarian and breast cancersKwai Wa Cheng1, John P Lahad1, Wen-lin Kuo2, Anna Lapuk2, Kyosuke Yamada2, Nelly Auersperg3, Jinsong Liu4, Karen Smith-McCune5, Karen H Lu6, David Fishman7, Joe W Gray2
& Gordon B Mills11
Department of Molecular Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
77054, USA. 2
Lawrence Berkley National Laboratory, Berkeley, California
94720, USA. 3
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia
V6H 3V5, Canada. 4
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA. 5
Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California
94143, USA. 6
Department of Gynecological Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA. 7
Department of Obstetrics and Gynecology, School of Medicine, New York University, New York, New York
10016, USA.
Correspondence should be addressed to Gordon B Mills gmills@mdanderson.orgHigh-density array comparative genomic hybridization (CGH)1 showed amplification of chromosome 1q22 centered on the RAB25 small GTPase2, which is implicated in apical vesicle trafficking3, 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.
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