The interaction of
annexin A6 (AnxA6) with membrane
phospholipids and either specific extracellular matrix (ECM) components or
F-actin suggests that it may influence cellular processes associated with rapid plasma membrane reorganization such as cell adhesion and motility. Here, we examined the putative roles of AnxA6 in adhesion-related cellular processes that contribute to
breast cancer progression. We show that
breast cancer cells secrete
annexins via the exosomal pathway and that the secreted
annexins are predominantly cell surface-associated. Depletion of AnxA6 in the invasive BT-549
breast cancer cells is accompanied by enhanced anchorage-independent cell growth but cell-cell cohesion, cell adhesion/spreading onto
collagen type IV or
fetuin-A, cell motility and invasiveness were strongly inhibited. To explain the loss in adhesion/motility, we show that
vinculin-based focal adhesions in the AnxA6-depleted BT-549 cells are elongated and randomly distributed. These focal contacts are also functionally defective because the activation of
focal adhesion kinase and the phosphoinositide-3
kinase/Akt pathway were strongly inhibited while the MAP
kinase pathway remained constitutively active. Compared with normal human breast tissues, reduced AnxA6 expression in
breast carcinoma tissues correlates with enhanced cell proliferation. Together this suggests that reduced AnxA6 expression contributes to
breast cancer progression by promoting the loss of functional cell-cell and/or cell-ECM contacts and anchorage-independent cell proliferation.