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Metastasis is the main cause of breast cancer morbidity and mortality. Processes that allow for tumor cell migration and invasion are important therapeutic targets. Here we demonstrate that receptor-interacting protein kinase 2 (RIP2), a kinase known to be involved in inflammatory processes, also has novel roles in cancer cell migration and invasion.    Methods  A total of six breast cancer expression databases, including The Cancer Genome Atlas, were assessed for  RIP2  expression among various clinical subtypes and its role as a prognostic biomarker. mRNA fluorescence  in situ  hybridization (FISH) for  RIP2  was performed on 17 stage III breast cancers to determine if there was a correlation between  RIP2  expression and lymph node involvement. RNA-interference was used to knock-down  RIP2  expression in MDA-MB-231, Htb126, SUM149PT, MCF7, T47D, and HCC1428 cells. Cell migration and invasion were measured  in vitro  by scratch/wound healing and transwell migration assays. A xenograft mouse model was used to assess tumor growth and chemosensitivity to docetaxel  in vivo  in MDA-MB-231 cells with and without  RIP2  small hairpin RNA knockdown. Western blot and immunofluorescence imaging were used to evaluate protein expressions.    Results  Interrogation of expression databases showed that  RIP2  expression is significantly over-expressed in triple-negative breast cancers (TNBC: estrogen-receptor (ER) negative, progesterone-receptor (PR) negative, Her2/neu- (Her2) negative), compared to other clinical subtypes. High  RIP2  expression correlates with worse progression-free survival using a combined breast cancer expression array dataset consisting of 946 patients. Multivariate analysis shows  RIP2  as an independent prognostic biomarker. Knock-down of  RIP2  significantly decreases migration in both scratch/wound healing and transwell migration assays in MDA-MB-231, Htb126, SUM149PT, MCF7, and T47D cells and is correlated with decreased Nuclear Factor-kappaB and c-Jun N-terminal kinase (JNK) activation. Finally,  RIP2  knock-down leads to increased sensitivity to docetaxel and decreased tumor mass and lung metastases in a xenograft mouse model.    Conclusion  These results highlight RIP2 as a pro-metastasis kinase in patients with advanced breast cancer. These results also illustrate a novel role for this kinase in addition to its known role in inflammation, and suggest that targeting RIP2 may improve outcomes in advanced breast cancer patients, in which it is overexpressed.

breast cancer research

Receptor-interacting protein kinase 2 promotes triple-negative breast cancer cell migration and invasion via activation of nuclear factor-kappaB and c-Jun N-terminal kinase pathways