July 5, 2010 A multi-disciplinary team of international researchers from Ghent University in Belgium, National Human Genome Research Institute (NHGRI) in the US, Imperial College London in the United Kingdom, and INSERM in France has uncovered a novel molecular pathway that regulates invasive growth and metastasis in estrogen receptor-positive breast cancer.
Cancers achieve invasive growth by delivering pro-invasive molecules into the tumor micro-environment, but the molecular mechanisms for the secretion of these proinvasive growth regulators remain largely unknown. One likely process involves release of vesicle content (exocytosis). Key players in exocytosis include the small Rab GTPases, which serve as molecular modulators of cellular vesicle membrane trafficking. Rab27B belongs to the family of secetory Rab GTPases, and controls the secretory process of vesicles.
The investigators demonstrated that over-expression of Rab27B in non-invasive breast cancer cell lines promoted cell cycle progression, proliferation and invasiveness of breast cancer cells in vitro. Mass spectrometry identified HSP90-alpha, a chaperone molecule, as a key pro-invasive growth regulator that was secreted in a Rab27B-dependent fashion into the micro-environment and was required for the activation of matrix metallo proteinase-2, a key player in breakdown of the extracellular matrix. In an in vivo xenograft mouse model, the investigators showed that invasive tumor growth and hemorrhagic ascites was induced by Rab27B.
To translate their research results from bench to bedside, the investigators studied the expression levels of Rab27B in primary breast cancer samples. Statistical analysis revealed that up-regulation of Rab27B was associated with lymph node metastasis and tumor differentiation grade in estrogen receptor-positive human breast tumors.
In conclusion, derailed Rab27B-mediated exocytosis regulates invasive growth and metastasis in ER-positive breast cancer cell lines, and increased expression is associated with poor prognosis in humans. Considerable therapeutic potential may reside in efforts to control Rab27B levels and to modulate Rab27B-regulated pathways through pharmacological or genetic interventions.
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- A. Hendrix, D. Maynard, P. Pauwels, G. Braems, H. Denys, R. Van den Broecke, J. Lambert, S. Van Belle, V. Cocquyt, C. Gespach, M. Bracke, M. C. Seabra, W. A. Gahl, O. De Wever, W. Westbroek. Effect of the Secretory Small GTPase Rab27B on Breast Cancer Growth, Invasion, and Metastasis. JNCI Journal of the National Cancer Institute, 2010; 102 (12): 866 DOI: 10.1093/jnci/djq153
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