Extracellular matrix (ECM)-related adhesion proteins are important in metastasis. Ras suppressor-1 (RSU-1), a suppressor of -transformation, is localized to cell⁻ECM adhesions where it interacts with the Particularly Interesting New Cysteine-Histidine rich protein (PINCH-1), being connected to Integrin Linked Kinase (ILK) and alpha-parvin (PARVA), a direct actin-binding protein. was also found upregulated in metastatic breast cancer (BC) samples and was recently demonstrated to have metastasis-promoting properties. In the present study, we transiently silenced in BC cells, MCF-7 and MDA-MB-231. We found that silencing leads to downregulation of Growth Differentiation Factor-15 (), which has been associated with both actin cytoskeleton reorganization and metastasis. silencing also reduced the mRNA expression of and cell division control protein-42 (), while increasing that of and regardless of the presence of GDF-15. However, the downregulation of actin-modulating genes , , Rho associated kinase-1 (), and following depletion was completely reversed by GDF-15 treatment in both cell lines. Moreover, complete rescue of the inhibitory effect of silencing on cell invasion was achieved by GDF-15 treatment, which also correlated with matrix metalloproteinase-2 expression. Finally, using a graph clustering approach, we corroborated our findings. This is the first study providing evidence of a functional association between and with regard to cancer cell invasion.