miR-181 elevates Akt signaling by co-targeting PHLPP2 and INPP4B phosphatases in luminal breast cancer
Strotbek M 1, Schmid S 1, Sànchez-Gonzàlez I 1, Boerries M 2,3, Busch H 2,3,4, Olayioye MA 1,5.
- 1Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
- 2Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Stefan-Meier Straße 17, 79104, Freiburg, Germany.
- 3German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im, Neuenheimer Feld 280, 69120, Heidelberg, Germany.
- 4Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
- 5Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.
Abstract
The PI3K-Akt pathway is one of the most commonly dysregulated cancer-associated signaling pathways. Here we report an oncogenic function for the miR-181 family in luminal breast cancer cells that involves Akt hyperactivation. We show that miR-181a and miR-181d post-transcriptionally suppress the expression of PHLPP2 and INPP4B phosphatases, resulting in elevated growth factor-induced Akt phosphorylation. Ectopic expression of miR-181a and miR-181d promoted S-phase entry and cell proliferation, which was reversed by pharmacological Akt inhibition. Importantly, the expression of miR-181 family members and PHLPP2/INPP2B are inversely correlated in primary human estrogen receptor-positive breast cancers, supporting the clinical relevance of our findings.