5868

RAB5A

RAB5A, member RAS oncogene family;RAB5A;RAB5A, member RAS oncogene family

RAS-associated protein RAB5A|ras-related protein Rab-5A

3p24-p22

protein-coding

OBJECTIVE: To study the expression and significance of RABEX-5 and RAB5 in human breast cancer. METHODS: In this study the expression of RABEX-5 and RAB5 mRNA and protein was detected by Immunohistochemical techniques, the reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot assay in 60 cases of breast cancer, 15 cases of breast fibroadenomas and 15 cases of normal breast tissue. The relationship of RABEX-5, RAB5 and the clinic pathological features was also analyzed. RESULTS: expression of RABEX-5 and RAB5 in breast cancer was obviously higher than that in breast fibroadenomas and normal breast tissue (P < 0.05). RABEX-5 and RAB5 expression level in tumor diameter (T) >5 cm group of human breast cancer was obviously higher than that in T < or =2 cm and 2 < T < or =5 cm group (P < 0.05). RABEX-5 and RAB5 expression level in axillary lymph node positive group was obviously higher than that in negative group (P < 0.05). However, there were no significant differences of RABEX-5 and RAB5 levels between HER-2 (+) group and HER-2 (-) group (P > 0.05), ER (-) group and ER (+) group (P > 0.05), PR (-) group and PR (+) group (P> 0.05), and in histological grade I, II and III, there also were no significant differences of RABEX-5 and RAB5 levels. The expression of RABEX-5 is correlated with RAB5 in both mRNA and protein level. CONCLUSION: RABEX-5 and RAB5 may be involved in the development of breast cancer metastasis.

The expression of Rab proteins has been associated with cancer. However, few data are available on Rab5A expression in human breast cancer or its impact on disease progression. First, we examined the functional role of Rab5A in breast cancer cells. The expression of Rab5A in MDA-MB-231 cells can be stimulated by epidermal growth factor in a dose-dependent manner. The epidermal growth factor-induced increase of Rab5A expression correlated well with enhanced migration in wound healing migration assays in these cells. Furthermore, we evaluated the expression of Rab5A in breast cancer specimens using immunohistochemical staining, then analyzed the relationship between the expression of Rab5A and clinicopathological parameters. The increased expression of Rab5A protein in 123 breast cancer samples was associated with higher histological grade (P = 0.004), more lymphovascular invasion (P = 0.027), more axillary lymph node (LN) metastasis (P = 0.008), and a higher number of axillary LN metastases (P = 0.043). Among 218 axillary LNs of more than 10 breast cancer patients with node metastases, 167 metastatic LNs were found to have increased Rab5A expression. Rab5A is associated with axillary LN metastasis in breast cancer patients.

The mechanisms by which tumor cells metastasize and the role of endocytic proteins in this process are not well understood. We report that overexpression of the GTPase RAB5A, a master regulator of endocytosis, is predictive of aggressive behavior and metastatic ability in human breast cancers. RAB5A is necessary and sufficient to promote local invasion and distant dissemination of various mammary and nonmammary tumor cell lines, and this prometastatic behavior is associated with increased intratumoral cell motility. Specifically, RAB5A is necessary for the formation of invadosomes, membrane protrusions specialized in extracellular matrix (ECM) degradation. RAB5A promotes RAB4- and RABENOSYN-5-dependent endo/exocytic cycles (EECs) of critical cargos (membrane-type 1 matrix metalloprotease [MT1-MMP] and beta3 integrin) required for invadosome formation in response to motogenic stimuli. This trafficking circuitry is necessary for spatially localized hepatocyte growth factor (HGF)/MET signaling that drives invasive, proteolysis-dependent chemotaxis in vitro and for conversion of ductal carcinoma in situ to invasive ductal carcinoma in vivo. Thus, RAB5A/RAB4 EECs promote tumor dissemination by controlling a proteolytic, mesenchymal invasive program.