title: Annexin A6 contributes to the invasiveness of breast carcinoma cells by influencing the organization and localization of functional focal adhesions.
abstract: 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.
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA. asakwe@mmc.edu
authors.forename: Amos M
authors.initials: AM
authors.lastname: Sakwe
authors.forename: Rainelli
authors.initials: R
authors.lastname: Koumangoye
authors.forename: Bobby
authors.initials: B
authors.lastname: Guillory
authors.forename: Josiah
authors.initials: J
authors.lastname: Ochieng
mesh_terms: D017317:Annexin A6 / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology; D002277:Carcinoma / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055354:Exosomes / Q000378:metabolism; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034622:RNA Interference
chemical_list: D017317:Annexin A6; D008565:Membrane Proteins