Abstract
Abstract Introduction: HuR, a ubiquitously expressed member of the Hu family, selectively binds and stabilizes ARE-containing mRNAs encoding proto-oncogenes, cell cycle regulators, cytokines and growth factors. The role of HuR and its cellular function in breast cancer remains unclear. In the present study, we aimed to provide new insights into the molecular and cellular implication of HuR in breast cancer. Materials and methods. We first constructed a set of anti-HuR ribozyme transgenes that targeted human HuR. Breast cancer cells were transfected with the transgene, in order to establish new sublines with HuR expression knocked down. Cell growth and invasiveness were investigated using in vitro cell models. The expression of cyclin-D1 and MMP2 were determined using immunocytochemistry, Western blotting and polymerase chain reaction. Results: Here, we show that MCF7 and MDA-MB-231 cells breast cancer cells stability transfected with a hammerhead ribozyme transgene specifically targeted to HuR (MCF7HuRKO and MDA-MB-231HuRKO) have a reduction in HuR expression both at mRNA and protein levels. Using these new sublines of breast cancer cells, the in vitro growth was evaluated. We showed that that HuR knockdown dramatically reduced cell growth in MCF7 cells (P < 0.001) and to a lesser degree reduced that in MDA MB 231 cells. We further demonstrated that reduction of HuR in MDA MB 231 cells (MDA-MB-231HuRKO) resulted in a significant reduction of the in vitro invasiveness in MDA-MB-231 cells (P < 0.001), although the same failed to occur to MCF-7 cells. Furthermore, we found that the decreased cell growth rate in MCF7 cells following HuR knockdown was seen together with a reduction in cyclin D1 transcript and protein levels. It was also interest to observe that the change in invasiveness in MDA-MB-231 cells after HuR knockdown was accompanied by a decrease in MMP-9 levels. Conclusion: Our study shows that targeting HuR can influences breast cancer cell growth and invasion and suggests a role for HuR in vitro in enhancing breast cancer cell growth and invasion. These changes may be facilitated through changes in the level of cyclin D1 and MMP-9. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-11.
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