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Grant support

We are fully indebted to Anna Castro and Thierry Lorca for reagents. We thank Marta Canamero, Alba de Martino and Manuel Morente for help with the histopathological analysis. We thank Giovanna Roncador for the generation of MASTL antibody. We also thank members of the Cell Division and Cancer Group for helpful discussions. M.A.F. was supported by a young investigator grant from the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2014-60442-JIN; co-financed by FEDER funds). M.S.F. was supported by a fellowship from the Ministry of Educacion, Cultura y Deporte, and B.S.-C. was supported by Fundacion La Caixa. The research described in the manuscript was funded in part by Pfizer. Work in the M.M. laboratory was supported by grants from the MINECO (SAF2012-38215), Consolider-Ingenio 2010 Programme (SAF2014-57791-REDC), Excellence Network CellSYS (BFU2014-52125-REDT), the OncoCycle Programme (S2010/BMD-2470) from the Comunidad de Madrid, Worldwide Cancer Research (WCR no. 15-0278), and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548).

Analysis of institutional authors

Sanz-Flores, MariaAuthorQuintela-Fandino, MiguelAuthor

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Article

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

Publicated to:CELL DEATH AND DIFFERENTIATION. 25 (5): 828-840 - 2018-05-01 25(5), DOI: 10.1038/s41418-017-0024-0

Authors: Alvarez-Fernandez, Monica; Sanz-Flores, Maria; Sanz-Castillo, Belen; Salazar-Roa, Maria; Partida, David; Zapatero-Solana, Elisabet; Ali, H Raza; Manchado, Eusebio; Lowe, Scott; VanArsdale, Todd; Shields, David; Caldas, Carlos; Quintela-Fandino, Miguel; Malumbres, Marcos

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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.

Keywords

AnimalsBreast neoplasmsCell line, tumorExpressionFemaleGene expression regulation, enzymologicGene expression regulation, neoplasticGene knockdown techniquesGreatwall kinaseHumansMastlMastl protein, humanMiceMice, nudeMicrotubule-associated proteinsMitosisMitotic exitNeoplasm proteinsPpp2ca protein, humanPpp2r2bProtein phosphatase 2Protein phosphatase 2aProtein serine-threonine kinasesRecurrenceTargetVulnerabilities

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal CELL DEATH AND DIFFERENTIATION due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2018, it was in position 27/298, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 2.54. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.32 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 10.81 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-03, the following number of citations:

  • WoS: 69
  • Scopus: 73
  • Europe PMC: 41
  • OpenCitations: 65

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-03:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 95.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 95 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 46.25.
  • The number of mentions on the social network X (formerly Twitter): 7 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United Kingdom; United States of America.