ARTICLE ABSTRACTDeregulated molecular signaling pathways are responsible for the altered adhesive, migratory, and invasive properties of cancer cells. The different breast cancer subtypes are characterized by the expression of distinct miRNAs, short non-coding RNAs that posttranscriptionally modulate the expression of entire gene networks. Profiling studies have revealed downregulation of miR149 in basal breast cancer. Here, we show that miR149 expression severely impairs cell spreading, migration, and invasion of basal-like breast cancer cells. We identify signaling molecules, including the small GTPases Rap1a and Rap1b, downstream of integrin receptors as miR149 targets, providing an explanation for the defective Src and Rac activation during cell adhesion and spreading upon miR149 expression. Suppression of cell spreading by miR149 could be rescued, at least in part, by expression of constitutively active Rac. Finally, we demonstrate that increased miR149 levels block lung colonization in vivo. On the basis of our findings, we propose that miR149 downregulation in basal breast cancer facilitates the metastatic dissemination of tumor cells by supporting aberrant Rac activation. Cancer Res; 74(18); 5256–65. ©2014 AACR.