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

Published version
Peer-reviewed

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Type

Article

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Authors

Álvarez-Fernández, Mónica 
Sanz-Flores, María 
Sanz-Castillo, Belén 
Salazar-Roa, María 
Partida, David 

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.

Description

Keywords

Animals, Breast Neoplasms, Cell Line, Tumor, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Mice, Mice, Nude, Microtubule-Associated Proteins, Neoplasm Proteins, Protein Phosphatase 2, Protein Serine-Threonine Kinases

Journal Title

Cell Death Differ

Conference Name

Journal ISSN

1350-9047
1476-5403

Volume Title

25

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (unknown)
European Commission (260791)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (CB4140)
Cancer Research UK (C14303/A17197)
Cancer Research UK (16942)
Cancer Research UK (25815)