Targeting a key promoter of multiple pro-metastatic pathways in breast cancer

Targeting breast cancer cell ability to spread to distant sites has considerable therapeutic potential. Cysteine-rich protein 2 (CRP2) is an actin cytoskeleton regulator, whose expression is associated with a greater risk of metastasis in breast cancer patients. We previous established that CRP2 is critically required for breast cancercell invasion and that its knockdown inhibits cancer cell dissemination in aggressive mouse models of breast cancer. Mechanism wise, CRP2 combines dual and complementary functions in the cytoplasm and the nucleus. In the cytoplasm, its actin crosslinking activity promotes formation of invadopodia, which are invasive membrane protrusions triggering extracellular matrix degradation and providing cancer with the ability to breach barriers and spread from the primary tumor to surrounding tissues. In the nucleus, CRP2 binds to transcription factors to activate expression of pro-invasive matrix metalloproteinases that are afterward trafficked to invadopodia for secretion. Finally, accumulating evidence suggests that CRP2 also stimulates matrix degradation activity of cancer-associated fibroblasts. Altogether our data put CRP2 forward as a unique promoter of the invasive behavior of breast cancer cells that simultaneously facilitates invadopodium formationand up-regulates expression of the key enzymes responsible for invadopodium activity in both the tumor and stroma compartments. The INTERACTINg project aims at developing a therapeutically relevant strategy to target CRP2 in metastatic breast cancer. Like many other LIM domain and cytoskeletal proteins, CRP2 biological activity relies on its ability to mediate protein-protein interactions. Accordingly, we propose to identifyrelevant CRP2 interacting partners using a proteomic approach, and to screen for drugs able to disrupt such interactions and interfere with breast cancer cell invasion and metastasi