Schematic summary of the role of RANKL-overexpression in promoting cancer cell adhesion. In LNCaPRANKL cells, RANKL overexpression induced the expression of α2 integrin and AP-4 transcription factor. The later may account for the suppressed AR expression. In 3-D suspension culture, α2β1 integrin was activated through RANKL expressed by PCa cells or soluble RANKL expressed by stromal cells in the bone microenvironment. This activation would elicit FAK and Akt phosphorylation, resulting in enhanced cell motility, adhesion and survival. α2β1 integrin activation was further enhanced through AP-4 downregulation, resulting in AR accumulation that could play a role in LNCaPRANKL cell adhesion to ColI. We propose a possible positive feedback loop (dotted line) between AR and integrin α2 regulation that is further enhanced under 3-D conditions to support cell anchoring and survival in the bone microenvironment.