article accepted in Cancer Research:
miR-149 functions as a tumor suppressor by controlling breast epithelial cell migration and invasion.
Bischoff A 1, Huck B 1, Keller B 1, Strotbek M 1, Schmid S 2, Boerries M 3, Busch H 4, Müller D 1, Olayioye MA 1*.
1 Institute of Cell Biology and Immunology, University of Stuttgart.
2 Institute of Cell Biology and Immunology, Universtiy of Stuttgart.
3 Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg.
4 Institute of Molecular Medicie, Albert-Ludwigs-University Freiburg.
* Corresponding author: Institute of Cell Biology and Immunology, University of
Stuttgart
monilola.olayioye@izi.uni-stuttgart.de.
Abstract:
Deregulated 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 microRNAs (miRNAs), short non-coding RNAs that post-transcriptionally modulate the expression of entire gene networks. Profiling studies have revealed down-regulation of miR-149 in basal breast cancer. Here we show that miR-149 expression severely impairs cell spreading, migration and invasion of basal-like breast cancer cells. We identify signaling molecules downstream of integrin receptors as miR-149 targets, including the small GTPases Rap1a and Rap1b, providing an explanation for the defective Src and Rac activation during cell adhesion and spreading upon miR-149 expression. Suppression of cell spreading by miR-149 could be rescued, at least in part, by expression of constitutively active Rac. Finally, we demonstrate that increased miR-149 levels block lung colonization in vivo. Based on our findings we propose that miR-149 downregulation in basal breast cancer facilitates the metastatic dissemination of tumor cells by supporting aberrant Rac activation.