Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer, and metastasis is a leading cause of mortality in these patients. Fibulin-3, a secreted extracellular matrix protein, has a pro-invasive role in other cancers. However, a role for fibulin-3 in TNBC invasion is unknown. We have previously shown that KISS1R signaling promotes TNBC cell invasion through EGFR and MMP-9 activity, via β-arrestin2. Thus, we hypothesized that KISS1R signaling promotes TNBC cell invasion via fibulin-3. Our clinical data suggests that plasma fibulin-3 levels are elevated in metastatic TNBC patients. Additionally, we found that invasive breast cancer cells have increased expression of fibulin-3 and treatment with kisspeptin, the KISS1R ligand, further increased fibulin-3 expression and secretion. Also, depletion of β-arrestins in TNBC cells decreased fibulin-3 expression. Furthermore, fibulin-3 depletion in TNBC cells inhibited cell invasiveness through decreased MMP-9 activity. These results identify fibulin-3 as a new signaling partner of KISS1R and as a potential anti-metastasis target in TNBC
