Enhanced intrinsic migration of aggressive breast cancer cells by inhibition of Cdc42 GTPase Free

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Rho family GTPases Rho, Rac and Cdc42 play pivotal role in regulating distinct cytoskeletal changes necessary for cell migration. Migration of most cell types has been shown to be positively regulated by each of these members. However, we have recently shown that Rac1 inhibition results in stimulation of intrinsic migration of highly aggressive breast cancer cells but inhibition of migration of non-metastatic or moderately metastatic cells ( Zuo et al. Biochem Biophys Res Commun 351: 361-367, 2006). Because Rac and Cdc42 share some common effectors we have further characterized in the present study, the effects of the role of inhibition of Cdc42 on the migratory abilities of number of breast cancer cell lines with differential degrees of tumorigenic and metastatic potentials. We found that siRNA-mediated down-regulation of Cdc42 in non-metastatic (MCF-7) or moderately metastatic (Hs578T) cell lines resulted in inhibition of intrinsic migration, whereas in highly metastatic cell lines (MDA-MB-231 and C3L5) this resulted in stimulation of migration along with actin cytoskeletal changes (such as increased stress fiber formation) that favor cell migration. Furthermore we found downregulation of Cdc42 significantly increased RhoA activity in highly metastatic cell lines but not in non-metastatic or moderately metastatic cell lines, which may partly account for the migration stimulation of highly metastatic cell lines following Cdc42 down-regulation. Further study is underway to investigate the role(s) of other signaling pathway(s) in this process.