Dissecting the Molecular Mechanism of RhoC GTPase Expression in the Normal and Malignant Breast.

摘要

Primary inflammatory breast cancer (IBC) accounts for approximately 3% of new breast cancers in the US. This form of locally advanced breast cancer is rapidly metastatic and, because of this disease's rapid progression, the effectiveness of aggressive multimodality treatment is limited; the 5-year disease-free, mean survival rate is less than 45%, making IBC the most lethal form of breast cancer. Here, we report that RhoC GTPase expression is regulated by the NfkB pathway. Specifically, p65 binds to and activates the RhoC promoter leading to increased RhoC mRNA expression and RhoC-mediated motility and invasion in IBC cell lines, but not control metastatic breast cancer cell lines. Additionally, we report that IBC has an additional copy of chromosome 1, possibly leading to an additional mechanism of increased gene expression. Finally, although we did not find any recurrent gene fusions in IBC by high throughput transcriptome sequencing, by microRNA array, we found that miR-31 and miR-31* are specifically downregulated in IBC cell lines. Taken together, we have identified several molecular alterations which drive the aggressive phenotype of IBC cell lines and propose that these may represent important targets for future studies of IBC.