Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genetic aberrations at chromosome 1q22.
Figure 2: RAB25 regulates cell proliferation and survival.
Figure 3: RAB25 regulates tumorigenicity.

Similar content being viewed by others

References

  1. Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat. Genet. 20, 207–211 (1998).

    Article  CAS  Google Scholar 

  2. 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).

    CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Shayesteh, L. et al. PI3KCA is implicated as an oncogene in ovarian cancer. Nat. Genet. 21, 99–102 (1999).

    Article  CAS  Google Scholar 

  5. 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).

    CAS  Google Scholar 

  6. Berchuck, A. & Carney, M. Human ovarian cancer of the surface epithelium. Biochem. Pharmacol. 54, 541–544 (1997).

    Article  CAS  Google Scholar 

  7. Anand, N. et al. Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nat. Genet. 31, 301–305 (2002).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Anzick, S.L. et al. AIB1, a steroid receptor co-activator amplified in breast and ovarian cancer. Science 277, 965–967 (1997).

    Article  CAS  Google Scholar 

  10. 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).

    CAS  Google Scholar 

  11. Patael-Karasik, Y. et al. Comparative genomic hybridization in inherited and sporadic ovarian tumors in Israel. Cancer Genet. Cytogenet. 121, 26–32 (2000).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. Zudaire, I. et al. Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas. Histopathology 40, 547–555 (2002).

    Article  CAS  Google Scholar 

  14. 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).

    Article  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. Schaner, M.E. et al. Gene expression patterns in ovarian carcinomas. Mol. Biol. Cell. 14, 4376–4386 (2003).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. 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).

    CAS  Google Scholar 

  19. Mor, O. et al. Molecular analysis of transitional cell carcinoma using cDNA microarray. Oncogene 22, 7702–7710 (2003).

    Article  CAS  Google Scholar 

  20. 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).

    CAS  Google Scholar 

  21. Liu, J. et al. A genetically defined model for human ovarian cancer. Cancer Res. 64, 1655–1663 (2004)

    Article  CAS  Google Scholar 

  22. Milhavet, O., Gary, D.S. & Mattson, M.P. RNA interference in biology and medicine. Pharmacol. Rev. 55, 629–648 (2003).

    Article  Google Scholar 

  23. Gross, A., McDonnell, J.M. & Korsmeyer, S.J. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911 (1999).

    Article  CAS  Google Scholar 

  24. Wei, M. et al. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

    Article  CAS  Google Scholar 

  25. Degenhardt, K., Chen, G., Lindsten, T. & White, E. BAX and BAK mediate p53-independent suppression of tumorigenesis. Cancer Cell 2, 193–203 (2002).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. 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).

    Article  Google Scholar 

  28. Kennedy, S.G. et al. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11, 701–713 (1997).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gordon B Mills.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1125

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing