Abstract
High-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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References
Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat. Genet. 20, 207–211 (1998).
Goldenring, J.R., Shen, K.R., Vaughan, H.D. & Modlin, I.M. Identification of a small GTP-binding protein, Rab25, expressed in the gastrointestinal mucosa, kidney, and lung. J. Biol. Chem. 268, 18419–18422 (1993).
Wang, X., Kumar, R., Navarre, J., Casanova, J.E. & Goldenring, J.R. Regulation of vesicle trafficking in Madin-Darby canine kidney cells by Rab11a and Rab25 . J. Biol. Chem. 275, 29138–29146 (2000).
Shayesteh, L. et al. PI3KCA is implicated as an oncogene in ovarian cancer. Nat. Genet. 21, 99–102 (1999).
Fukushi, Y., Sato, S., Yokoyama, Y., Kudo, K., Maruyama, H., & Saito, Y. Detection of numerical aberrations in chromosome 17 and c-erbB2 gene amplification in epithelial ovarian cancer using recently established dual color FISH. Eur. J. Gynecol. Oncol. 22, 23–25 (2001).
Berchuck, A. & Carney, M. Human ovarian cancer of the surface epithelium. Biochem. Pharmacol. 54, 541–544 (1997).
Anand, N. et al. Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nat. Genet. 31, 301–305 (2002).
Cheng, J.Q. et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl. Acad. Sci. USA 89, 9267–9271 (1992).
Anzick, S.L. et al. AIB1, a steroid receptor co-activator amplified in breast and ovarian cancer. Science 277, 965–967 (1997).
Suzuki, S. et al. An approach to analysis of large-scale correlations between genome changes and clinical endpoints in ovarian cancer. Cancer Res. 60, 5382–5385 (2000).
Patael-Karasik, Y. et al. Comparative genomic hybridization in inherited and sporadic ovarian tumors in Israel. Cancer Genet. Cytogenet. 121, 26–32 (2000).
Kiechle, M., Jacobsen, A., Schwarz-Boeger, U., Hedderich, J., Pfisterer, J. & Arnold, N. Comparative genomic hybridization detects genetic inbalance in primary ovarian carcinomas as correlated with grade of differentiation. Cancer 91, 534–540 (2001).
Zudaire, I. et al. Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas. Histopathology 40, 547–555 (2002).
Lu, Y.J., Hing, S., Williams, R., Pinkerton, R., Shipley, J. & Pritchard-Jones, K. UK Children's Cancer Study Group Wilms' tumor group. Chromosome 1q expression profiling and relapse in Wilms' tumour. Lancet 9330, 385–386 (2002).
Lu, K.H. et al. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin. Cancer Res. 10, 3291–3300 (2004).
Schaner, M.E. et al. Gene expression patterns in ovarian carcinomas. Mol. Biol. Cell. 14, 4376–4386 (2003).
Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. Sci. USA 100, 8418–8423 (2003).
Calvo, A. et al. Alterations in gene expression profiles during prostate cancer progression: functional correlations to tumorigenicity and down-regulation of selenoprotein-P in mouse and human tumors. Cancer Res. 62, 5325–5335 (2002).
Mor, O. et al. Molecular analysis of transitional cell carcinoma using cDNA microarray. Oncogene 22, 7702–7710 (2003).
Wang, W. et al. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62, 6278–6288 (2002).
Liu, J. et al. A genetically defined model for human ovarian cancer. Cancer Res. 64, 1655–1663 (2004)
Milhavet, O., Gary, D.S. & Mattson, M.P. RNA interference in biology and medicine. Pharmacol. Rev. 55, 629–648 (2003).
Gross, A., McDonnell, J.M. & Korsmeyer, S.J. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911 (1999).
Wei, M. et al. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).
Degenhardt, K., Chen, G., Lindsten, T. & White, E. BAX and BAK mediate p53-independent suppression of tumorigenesis. Cancer Cell 2, 193–203 (2002).
Lu, Y. et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 18, 7034–7045 (1999).
Mills, G.B. et al. Role of abnormalities of PTEN and the phosphatidylinositol 3′ kinase pathway in breast and ovarian tumorigenesis, prognosis and therapy. Semin. Oncol. 28, S125–S141 (2001).
Kennedy, S.G. et al. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11, 701–713 (1997).
Delcroix, J.D., Valletta, J.S., Wu, C., Hunt, S.J., Kowal, A.S. & Mobley, W.C. NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39, 69–84 (2003).
Acknowledgements
KWC was supported by the Odyssey Program of the Houston Endowment Scientific Achievement award from MD Anderson Cancer Center. We thank N. E. Atkinson's group for help and advice in statistical analysis. We thank R. Lapushin and H. Hall for their support. We thank R. Trost for obtaining patient follow up. We thank the staffs from the MD Anderson Cancer Center and University of California San Francisco ovarian tumor bank for providing ovarian carcinomas. This work is supported by National Institutes of Health SPORE (P50-CA83639) and PPG-PO1 CA64602 to GBM and JWG and P30 grant CA16672-28.
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Supplementary information
Supplementary Fig. 1
RAB25 gene expression is associated with decreased overall survival in stage I–IV serous epithelial ovarian cancer patients. (PDF 16 kb)
Supplementary Fig. 2
RAB25 gene expression is associated with decreased disease free period in breast cancer patients, using data acquired from the Stanford breast cancer data set19. (PDF 17 kb)
Supplementary Fig. 3
Effect of RAB25 stable expression on cell proliferation in 1% or 10% fetal bovine serum containing media. (PDF 29 kb)
Supplementary Fig. 4
Knock down of RAB25 mRNA expression by RNA interference (RNAi) decreases cell number in A2780, OVCAR3, MCF-7 and in RAB25 stable transfected A2780 cells. (PDF 161 kb)
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Cheng, K., Lahad, J., Kuo, Wl. et al. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med 10, 1251–1256 (2004). https://doi.org/10.1038/nm1125
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DOI: https://doi.org/10.1038/nm1125
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