Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer.

Mónica Álvarez-Fernández,Elisabet Zapatero-Solana,Belén Sanz-Castillo,Todd Vanarsdale,Miguel Quintela-Fandino,Scott Lowe,María Salazar-Roa,Eusebio Manchado,María Sanz-Flores,David Partida,David Shields,Carlos Caldas,H Raza Ali,Marcos Malumbres

doi:10.1038/s41418-017-0024-0

Abstract

PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase MASTL (also known as Greatwall). During cell division, inhibition of PP2A-B55 by MASTL is required to maintain the mitotic state, whereas inactivation of MASTL and PP2A reactivation is required for mitotic exit. Despite its critical role in cell cycle progression in multiple organisms, its relevance as a therapeutic target in human cancer and its dependence of PP2A activity is mostly unknown. Here we show that MASTL overexpression predicts poor survival and shows prognostic value in breast cancer patients. MASTL knockdown or knockout using RNA interference or CRISPR/Cas9 systems impairs proliferation of a subset of breast cancer cells. The proliferative function of MASTL in these tumor cells requires its kinase activity and the presence of PP2A-B55 complexes. By using a new inducible CRISPR/Cas9 system in breast cancer cells, we show that genetic ablation of MASTL displays a significant therapeutic effect in vivo. All together, these data suggest that the PP2A inhibitory kinase MASTL may have both prognostic and therapeutic value in human breast cancer.

Highlights

Introductionphosphatase 2A (PP2A) function as a multimeric complex containing a catalytic (C), scaffold (A) and regulatory (B) subunit
MASTL depletion differentially affects proliferation in breast cancer cell lines Given the potential relevance of MASTL-phosphatase 2A (PP2A)/B55 pathway in breast cancer, we first analyzed MASTL expression and the consequences of its depletion in a panel of breast tumor cell lines, including both hormone-positive/luminal (T47D, MCF7, BT-483, EVSA-T, MDA-MB-415) and triple-negative/ basal-like (MDA-MB-231, BT-549, MDA-MB-468, HCC1143) subtypes
PP2A is a major tumor suppressor whose activity is inhibited by different means in human cancer

Summary

Introduction

PP2A function as a multimeric complex containing a catalytic (C), scaffold (A) and regulatory (B) subunit. Mutations and somatic alterations of the PP2A scaffold and regulatory subunits have been detected in several types of human cancer [1, 2]. Deletions in PPP2R2A, the gene encoding the α isoform of the PP2A regulatory subunit B55, are amongst the most frequent events in luminal-like breast cancer and define a sub-group of aggressive tumors [3, 4]. PPP2R2B, encoding B55β, is frequently inactivated by methylation in breast tumors [5] and a genetic variant in this gene associates with altered breast cancer risk and recurrence [6], suggesting that PP2A-B55 complexes may play a tumor suppressor role in breast cancer

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