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

Michaela Strotbek; Simone Schmid; Ismael Sánchez-González; Melanie Boerries; Hauke Busch; Monilola A Olayioye

doi:10.1002/ijc.30661

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

Int J Cancer. 2017 May 15;140(10):2310-2320. doi: 10.1002/ijc.30661. Epub 2017 Mar 11.

Authors

Michaela Strotbek¹, Simone Schmid¹, Ismael Sánchez-González¹, Melanie Boerries^{2

3}, Hauke Busch^{2

3

4}, Monilola A Olayioye^{1

5}

Affiliations

¹ Institute of Cell Biology and Immunology, University of Stuttgart, 70569, Stuttgart, Germany.
² Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany.
³ German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
⁴ Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
⁵ Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany.

PMID: 28224609
DOI: 10.1002/ijc.30661

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 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.

Keywords: PI3K-Akt pathway; breast cancer; lipid and protein phosphatases; microRNA/miRNA; receptor tyrosine kinase signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Blotting, Western
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Cell Cycle
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Humans
MicroRNAs / genetics*
Phosphoprotein Phosphatases / genetics
Phosphoprotein Phosphatases / metabolism*
Phosphoric Monoester Hydrolases / genetics
Phosphoric Monoester Hydrolases / metabolism*
Phosphorylation
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tumor Cells, Cultured

Substances

MIRN-181 microRNA, human
MicroRNAs
RNA, Messenger
Proto-Oncogene Proteins c-akt
PHLPP2 protein, human
Phosphoprotein Phosphatases
Phosphoric Monoester Hydrolases
phosphatidylinositol-3,4-bisphosphate 4-phosphatase