Research project 1: The role of Rab GTPases in cancer progression.
Vesicle exocytosis, controlled by secretory GTPases such as Rab27B, delivers critical pro-invasive growth regulators into the tumor microenvironment. The biological role and expression status of Rab27B in breast cancer was unknown. Rab27B-upregulation promoted G1/S phase cell cycle transition and increased proliferation, F-actin reorganization and invasion in cell culture, and invasive tumor growth and haemorrhagic ascites in a xenograft mouse model (at 10 weeks, survival of MCF-7 GFP vs GFP-Rab27B injected mice was 100% vs 62.5%, P=0.0307). Proteomic analysis of purified Rab27B-secretory vesicles and the secretome of exogenous Rab27B-expressing breast cancer cells identified heat shock protein (HSP)90α as key pro-invasive growth regulator. HSP90α secretion occurred in a Rab27B-dependent manner and was required for matrix metalloproteinase (MMP)-2 activation. All Rab27B-mediated functional responses were GTP- and geranylgeranyl-dependent. Endogenous Rab27B mRNA and protein, but not Rab3D and Rab27A mRNA, associated with lymph node metastasis (P=0.0002) and differentiation grade (P=0.0014) in ER-positive human breast tumors. In conclusion, Rab27B regulates invasive growth and metastasis in ER-positive breast cancer.
Research project 2: The role of the adipokine resistin in breast cancer development.
Only a few years ago, adipose tissue was merely seen as a storage place for excessive energy. Now adipose tissue is known to be an active endocrine organ that produces a whole spectrum of adipocytokines. Adipocytes are one of the most abundant stromal celtypes that surround the breast cancer cells en they play a key role in the stromal-ductal and epithelial cell-cell interactions in the normal breast tissue. Different investigators rapported a strong interaction between breast cancer cells and the surrounding stromal cells. Recently, many studies relate certain adipocytokines (leptin, adiponectin, …) to breast cancer. Further, obesitas is linked with an increased risk of postmenopausal breast cancer. Resistin is a recently identified adipocytokine that blocks de glucose uptake in skeletal muscles. In mice, there was a strong relation between resistin, obesitas and insulin resistance. An ELISA performed in human serum showed a positive correlation between the level of serum resistin and the body mass index in healthy persons, as in patients with type 2 diabetes. Other studies describe an activation of endothelial cells by resistin. It is clear that resistin has many biological functions but the relationship with breast cancer has barely been investigated.
In collaboration with the Laboratory of Experimental Cancer Research an in vivo experiment showed that resistin was able to slow down the growth of xenograft breast cancer tumors in a dose-dependent manner. One of the underlying mechanism could be revealed. Resistin upregulates SOCS-3 expression, leading to a downregulation of the Akt-pathway, which represents an important survival-signal.
Preliminary research showed that resistin can influence angiogenesis. Maybe this represents a secondary mechanism to explain the growth-inhibition? Or perhaps resistin creates a disbalance between TIMP’s and MMP’s, causing changes in the extracellular matrix and influencing tumor growth?
Not only resistin but also other adipokines and correlations between different adipokines play a role in the breast cancer process. The serum concentration and adipose tissue expression of leptin, adiponectin and resistin will be determined and the relation of these adipokines regarding breast cancer will be investigated.
The stromal environment plays an important role in the chemosensitivity of breast cancer cells. Is this interaction influenced by resistin?
Hendrix A, Maynard D, Pauwels P, Braems G, Denys H, Van den Broecke R, Lambert J, Van Belle S, Cocquyt V, Gespach C, Bracke M, Seabra MC, Gahl WA, De Wever O and Westbroek W. The secretory small GTPase Rab27B regulates invasive tumor growth and metastasis through extracellular HSP90 alpha. Last two authors contributed equally. The Journal of the National Cancer Institute, 2010, in press.
Research Techniques and Infrastructure
Invasie models, xenograft mouse models
Mass spectrometry, confocal microscopy
Laboratory of Experimental Cancer Research: Dr. Apr. O. De Wever, Prof. dr. M. Bracke
Department of Gynaecology: Prof. dr. G. Braems, Prof. dr. R. Van den Broecke
Department of Anatomical Pathology: Dr. K. Lambein
NHGRI: National Institutes of Health, Bethesda, US: Dr. W. Westbroek, Dr. W. Gahl