BRCA2 is a multifunctional
tumor suppressor protein which plays critical roles in DNA repair, transcription, and cell proliferation, and the loss of which has been linked to the biology of several types of
cancers. Here, on prostate
adenocarcinoma specimens from 80 patients, we demonstrate that
BRCA2 protein is lost in
carcinoma cells compared to normal and hyperplastic prostate epithelium. Using highly metastatic
prostate cancer PC-3 cells, we show that while BRCA2 depletion by
small-interfering RNA promoted migration onto the
extracellular matrix proteins fibronectin,
laminin, and
collagens, as well as invasion through the reconstituted basement membrane matrix
Matrigel by more than 140%, recombinant BRCA2 overexpression decreased both phenomena by 57-80% and changed cell morphology from angular and spindle to round and compact. The BRCA2 inhibitory effect on
cancer cell migration and invasion resulted from down-regulation of
matrix metalloproteinase (MMP)-9
protein levels due to increased MMP-9 proteolysis, and was signaled through inhibition of
PI3-kinase/AKT and activation of MAPK/ERK pathway. In BRCA2-overexpressing PC-3 cells, transient transfection with a constitutively active
PI3-kinase mutant or treatment with the MAPK/ERK inhibitor
PD98059 rescued MMP-9 levels and restored the migratory and invasive capabilities. Consistently,
PI3-kinase inhibition with a dominant-negative mutant or MAPK/ERK activation with a gain-of-function mutant reduced MMP-9 levels and prevented migration and invasion in wild-type PC-3 cells. These results provide novel evidence showing that a functional
BRCA2 protein may limit the metastatic potential of neoplastic cells by down-regulating MMP-9 production through inhibition of
PI3-kinase/AKT and activation of MAPK/ERK, effectively hindering
cancer cell migration and invasion.