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C29 CD44 potentiates the primary adhesion of breast cancer cells to human bone marrow endothelial cells (BMECs). The aim of this study was to establish the distal events underpinning CD44-initiated adhesion, using parental and bone-homing (BO) clones of the MDA-MB-231 breast cancer cell line. MDA-MB-231BO cells displayed increased CD44 expression and adhesion to both BMECs and fibronectin, relative to parental cells. MDA-MB-231BO cells also displayed increased expression and activation of the β1-integrin subunit. In addition the bone homing cells exhibited elevated constitutive phosphorylation of the kinases Src and FAK and the cytoskeletal proteins cortactin and paxillin relative to the parental cells. Stimulation of MDA-MB-231BO cells with the CD44 ligand hyaluronan (HA) induced an increase in the expression of the β1-integrin chain, FAK and paxillin and furthermore, promoted a rapid increase in the activation status of the β1-integrin subunits, Src, cortactin and paxillin in these cells. The HA-induced phosphorylation of paxillin was attenuated by depletion of CD44 and cortactin expression using selective RNAi strategies, suggesting that it is a downstream target of HA-CD44-cortactin signaling. MDA-MB-231BO cell adhesion to fibronectin or to hBMECs was attenuated by RNAi-mediated suppression of CD44, cortactin and paxillin expression or following administration of two neutralizing antibodies that inhibit β1-integrin and α4β1-integrin receptor signaling. Antibody-based inhibition of integrin signaling also attenuated the HA-induced phosphorylation of cortactin and paxillin suggesting that these proteins constitute a signaling cascade activated downstream of a CD44-initiated, integrin-dependent process. Our results describe a molecular pathway promoting cytoskeletal reorganization that is activated downstream of a CD44 induced, integrin-dependent event and which is critical to efficient breast cancer cell adhesion to hBMECs.

breast cancer research

Characterization of a cytoskeletal signaling pathway underpinning CD44-initiated, integrin-mediated adhesion of breast cancer cells to bone marrow endothelium