Emerging Role of RAB GTPases in Cancer and Human Disease

Abstract

Emerging evidence implicates alterations in the RAB small GTPases and their associated regulatory proteins and effectors in multiple human diseases including cancer. We have recently shown that RAB25, located at chromosome 1q22, is amplified at the DNA level and overexpressed at the RNA level in ovarian and breast cancer. These changes correlated with a worsened outcome in both diseases. In addition, enforced expression of RAB25 in both breast and ovarian cancer cells decreased apoptosis and increased proliferation and aggressiveness in vivo, potentially explaining the worsened prognosis. A better understanding of genetic alterations as well as the physiologic and pathophysiologic roles of RAB GTPases may open new opportunities for therapeutic intervention and better outcomes. (Cancer Res 2005; 65 (7): 2516-9) Molecular Profiling and Identification of Genetic Defect in CancersCancer is caused by abnormalities in DNA sequence, copy number, rearrangements, or expression. The accumulation of multiple changes in critical genes within a single cell is required to escape from normal controls on cell growth and proliferation, allowing development into a clinically evident tumor (1). Understanding the molecular basis of tumorigenesis is the key to better diagnosis, prognosis, and treatment for cancer. Large-scale profiling of gene expression and genomic alterations has revealed multiple differences between normal and malignant cells, specific genetic and cellular changes that occur at each stage of tumor progression, and aberrations that can distinguish cancers of different origins and metastatic potential. This genome-wide information will facilitate the identification of new diagnostic markers, prognostic and predictive information, and novel molecular targets. This, in turn, will lead to the development, validation, and implementation of new, less toxic, and more effective drugs.Array comparative genomic hybridization (2) provides a robust, sensitive, and high-resolution approach to the identification of regions of DNA copy number increase and decrease in tumors. These copy number aberrations are selected during tumorigenesis, contributing to the behavior of tumors, and indeed can be predictive of patient outcome (3). Multiple chromosomal amplifications implicated in the pathophysiology of ovarian and breast carcinomas have been detected (4, 5). The identification of the candidate genes driving the development of the DNA copy number aberrations in cancer has progressed at a slow rate. However, new technologies are likely to increase the pace. We, for example, have extensively characterized an amplicon present in ovarian cancer on chromosome 3q, finding that the PIK3CA gene expressing the catalytic a subunit of phosphoinositide-3-kinase is amplified in ovarian cancer and is a critical regulator of different functions in ovarian cancer (6). This, along with other developments, has contributed to the phosphoinositide-3-kinase pathway being identified as a prime candidate for the development of novel therapies. R...

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

“…The third included genes involved in cellular trafficking VPS45A, ARF1, LYST, CCT3 or basic cellular metabolism CA14, ALDH9A1. Note that RAB25 has also been related to the activation of protein trafficking between the membrane and the endoplasmic reticulum (Cheng et al, 2005). Similar functional groups have been observed in other selections of genes involved in genomic gains or amplifications, thus indicating the importance of activated transcription, increased signalling and protein trafficking or catabolism in cancer.…”

Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

“…Finally, ICMT-mediated methylation is also needed for the function of a subset of Rab family small GTPases, regulators of vesicular trafficking (Leung et al, 2006), thus expanding the candidate targets for ICMT inhibitors beyond CAAX-terminating proteins. Some Rab proteins have also been implicated in oncogenesis (Cheng et al, 2005).…”

The Lipid Kinase PI4KIIIβ Is Highly Expressed in Breast Tumors and Activates Akt in Cooperation with Rab11a

“…Because we have not observed any alterations in PI (3,4,5)P 3 abundance following Rab11a knockdown, we speculate that Rab11a may serve as an endosomal scaffolding nexus for proteins that activate and phosphorylate Akt directly and that increased expression of PI4KIIIb increases the number of these scaffolding complexes. Rab GTPases have been previously linked to breast cancer oncogenesis in their role as central regulators of cell trafficking (61)(62)(63).…”