RNA polymerase II cofactor PC4 was found highly expressed in more invasive breast cancer cell lines and up-regulated during clinical progression of carcinoma in situ to invasive and metastatic carcinomas. Here we investigate the functional role of PC4 in breast cancer cell invasion and breast cancer progression. PC4 protein levels were elevated in invasive breast carcinoma compared with normal breast epithelia. Analysis of microarray datasets for breast cancer survival cohorts showed that higher SUB1 gene expression (mRNA) was associated with higher relapses in basal tumours with emphasis on brain relapses. Consistently, we have observed up-regulated expression of PC4 in metastatic samples compared to primary tumours in matched primary and brain metastasis breast cancer pairs. Depletion of PC4 in invasive breast cancer cell lines abolished cell invasion. Collectively, these data identify PC4 as a potentially new marker in breast cancer progression and metastasis and provide a rationale for novel therapeutic target.