miR-181 elevates Akt signaling by co-targeting PHLPP2 and INPP4B phosphatases in luminal breast cancer

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 posttranscriptionally 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. What's new? The PI3K-Akt pathway is one of the most commonly dysregulated signaling pathways in cancer. Here, the authors reveal molecular mechanisms whereby the miR-181 family members contribute to PI3K-Akt pathway activation. The increased expression of miR-181 family members in luminal breast cancer inversely correlates with the expression of PHLPP2 and INPP4B, both tumor-suppressive phosphatases that negatively regulate the PI3K survival pathway. Experimental evidence shows that miR-181 overexpression hyperactivates PI3K-Akt signaling and stimulates growth through the pathway. Combining antiestrogen treatment with PI3K pathway inhibitors may thus represent a promising strategy for the treatment of luminal breast cancers with high miR-181 expression levels.