By combining in vivo and in vitro experiments we demonstrate here that CYR61 promotes lung metastasis of triple-negative breast cancer by facilitating two events relevant to the late steps of metastatic dissemination: firstly, by enhancing extravasation of cancer cells into the lung and, secondly, by conferring resistance to anoikis, at least in part, through the activation of AMPKα pathway but not through AKT, FAK or ERK1/2 signaling. Here, PTK2 is linked to triple-negative breast carcinoma.