Little is known about the molecular and genetic events that underlie the highly aggressive nature of ovarian cancers. Using comparative genomic hybridization (CGH) to identify amplified regions of tumour DNA samples, Gordon Mills and colleagues have identified the small GTPase RAB25 as an important mediator of ovarian tumour growth and progression.

Chromosome 1q has been previously shown to be frequently amplified in ovarian and breast cancers, but no one has identified the specific genetic elements in this region that might underlie tumour initiation or progression. Using CGH analysis, Mills and colleagues identified a 1.1 megabase region located at chromosome 1q22 that was amplified in 28 of 52 (54%) of advanced serous epithelial ovarian cancers. In examining DNA samples of patients with ovarian cancer, they observed that after surgery and chemotherapy, patients with increased copy numbers of this region either failed to enter a disease-free state or experienced a much shorter term of disease-free survival, compared with other patients with ovarian cancer.

Chromosome 1q22 contains 34 genes, so which of these might be associated with disease progression? By analysing microarray data and mRNA expression levels of these genes, the authors observed that only the RAB25 mRNA levels were markedly increased in most (89%) ovarian tumour samples. Similar findings were confirmed in an independent data set. The increase in RAB25 expression was more commonly detected in late-stage (stage III and IV) than in early-stage tumours, and overexpression was associated with decreased time of patient survival. The gene was also found to be upregulated in about 50% of breast tumour samples, compared with normal tissue, and had been previously reported to be upregulated in prostate and bladder tumours.

Is RAB25 upregulation sufficient to promote tumour growth or progression? Mills and colleagues overexpressed the gene in ovarian and breast cancer cell lines, and showed that it protected cells from apoptosis and anoikis induction. These cell-survival-promoting effects were mediated through activation of the phosphaditylinositol 3-kinase (PI3K) signalling pathway, indicated by the presence of phosphorylated AKT, leading to reduced expression of pro-apoptotic BCL2 family members. Inhibition of RAB25 expression by RNA interference reversed this effect, causing cells to undergo apoptosis. RAB25 is a well-known regulator of vesicle trafficking and cytoskeletal organization, but further studies are required to determine how it might interact with this anti-apoptotic PI3K signalling pathway.

What are the effects of RAB25 on in vivo tumour growth? Overexpression of RAB25 in ovarian cancer cell lines caused larger, more aggressive tumours to form when cells were injected into nude mice. The gene was not able to transform non-tumorigenic ovarian epithelial cells, however, indicating that it is required for progression, but not initiation, of ovarian and possibly breast cancer.