High nuclear MSK1 is associated with longer survival in breast cancer patients

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Abstract

Purpose

Mitogen- and stress-activated kinases (MSKs) are important substrates of the mitogen-activated protein kinase (MAPK)-activated protein kinase family. MSK1 and MSK2 are both nuclear serine/threonine protein kinases, with MSK1 being suggested to potentially play a role in breast cancer cell proliferation, cell cycle progression, cell migration, invasion and tumour growth. The aim of the current study was to assess MSK1 protein expression in breast cancer tumour specimens, evaluating its prognostic significance.

Methods

A large cohort of 1902 early stage invasive breast cancer patients was used to explore the expression of MSK1. Protein expression was examined using standard immunohistochemistry on tissue microarrays.

Results

Low MSK1 protein expression was associated with younger age ( P = 0.004), higher tumour grade ( P < 0.001), higher Nottingham Prognostic Index scores ( P = 0.007), negative ER ( P < 0.001) and PR ( P < 0.001) status, and with triple-negative ( P < 0.001) and basal-like ( P < 0.001) phenotypes. Low MSK1 protein expression was significantly associated with shorter time to distant metastasis ( P < 0.001), and recurrence ( P = 0.013) and early death due to breast cancer ( P = 0.01). This association between high MSK1 expression and improved breast cancer-specific survival was observed in the whole cohort ( P = 0.009) and in the HER2-negative and non-basal like tumours ( P = 0.006 and P = 0.024, respectively). Multivariate analysis including other prognostic variables indicated that MSK1 is not an independent marker of outcome.

Conclusions

High MSK1 is associated with improved breast cancer-specific survival in early stage invasive breast cancer patients, and has additional prognostic value in HER2-negative and non-basal like disease. Although not an independent marker of outcome, we believe such findings and significant associations with well-established negative prognostic factors (age, grade, Nottingham Prognostic Index, hormone receptor status, time to distant metastasis, recurrence and triple-negative/basal-like status) warrant further examination and validation in independent patient cohorts.

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Most cited references 16

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REporting recommendations for tumour MARKer prognostic studies (REMARK)

L M McShane, D Altman, W Sauerbrei … (2005)

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

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Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB.

M Deák, A D Clifton, L Lucocq … (1998)

We have identified a novel mitogen- and stress-activated protein kinase (MSK1) that contains two protein kinase domains in a single polypeptide. MSK1 is activated in vitro by MAPK2/ERK2 or SAPK2/p38. Endogenous MSK1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to UV radiation, and oxidative and chemical stress. The activation of MSK1 by growth factors/phorbol esters is prevented by PD 98059, which suppresses activation of the MAPK cascade, while the activation of MSK1 by stress stimuli is prevented by SB 203580, a specific inhibitor of SAPK2/p38. In HeLa, PC12 and SK-N-MC cells, PD 98059 and SB 203580 are both required to suppress the activation of MSK1 by TNF, NGF and FGF, respectively, because these agonists activate both the MAPK/ERK and SAPK2/p38 cascades. MSK1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates CREB at Ser133 with a Km value far lower than PKA, MAPKAP-K1(p90Rsk) and MAPKAP-K2. The effects of SB 203580, PD 98059 and Ro 318220 on agonist-induced activation of CREB and ATF1 in four cell-lines mirror the effects of these inhibitors on MSK1 activation, and exclude a role for MAPKAP-K1 and MAPKAP-K2/3 in this process. These findings, together with other observations, suggest that MSK1 may mediate the growth-factor and stress-induced activation of CREB.

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High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses.

Douglas MacMillan, R W Blamey, E Paish … (2005)

Recent studies on gene molecular profiling using cDNA microarray in a relatively small series of breast cancer have identified biologically distinct groups with apparent clinical and prognostic relevance. The validation of such new taxonomies should be confirmed on larger series of cases prior to acceptance in clinical practice. The development of tissue microarray (TMA) technology provides methodology for high-throughput concomitant analyses of multiple proteins on large numbers of archival tumour samples. In our study, we have used immunohistochemistry techniques applied to TMA preparations of 1,076 cases of invasive breast cancer to study the combined protein expression profiles of a large panel of well-characterized commercially available biomarkers related to epithelial cell lineage, differentiation, hormone and growth factor receptors and gene products known to be altered in some forms of breast cancer. Using hierarchical clustering methodology, 5 groups with distinct patterns of protein expression were identified. A sixth group of only 4 cases was also identified but deemed too small for further detailed assessment. Further analysis of these clusters was performed using multiple layer perceptron (MLP)-artificial neural network (ANN) with a back propagation algorithm to identify key biomarkers driving the membership of each group. We have identified 2 large groups by their expression of luminal epithelial cell phenotypic characteristics, hormone receptors positivity, absence of basal epithelial phenotype characteristics and lack of c-erbB-2 protein overexpression. Two additional groups were characterized by high c-erbB-2 positivity and negative or weak hormone receptors expression but showed differences in MUC1 and E-cadherin expression. The final group was characterized by strong basal epithelial characteristics, p53 positivity, absent hormone receptors and weak to low luminal epithelial cytokeratin expression. In addition, we have identified significant differences between clusters identified in this series with respect to established prognostic factors including tumour grade, size and histologic tumour type as well as differences in patient outcomes. The different protein expression profiles identified in our study confirm the biologic heterogeneity of breast cancer and demonstrate the clinical relevance of classification in this manner. These observations could form the basis of revision of existing traditional classification systems for breast cancer.

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Author and article information

Contributors

Stewart G. Martin:

ORCID: http://orcid.org/0000-0002-2810-2338

+44 (0)115 823 1846 , stewart.martin@nottingham.ac.uk

Journal

Journal ID (nlm-ta): J Cancer Res Clin Oncol

Journal ID (iso-abbrev): J. Cancer Res. Clin. Oncol

Title: Journal of Cancer Research and Clinical Oncology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0171-5216

ISSN (Electronic): 1432-1335

Publication date (Electronic): 11 January 2018

Publication date PMC-release: 11 January 2018

Publication date (Print): 2018

Volume: 144

Issue: 3

Pages: 509-517

Affiliations

[1 ]University of Nottingham, Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK

[2 ]University of Nottingham, Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK

Author information

Stewart G. Martin http://orcid.org/0000-0002-2810-2338

Article

Publisher ID: 2579

DOI: 10.1007/s00432-018-2579-7

PMC ID: 5816103

PubMed ID: 29327245

SO-VID: de29d28f-66c3-479e-9e9c-35de5e2d2812

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 21 December 2017

Date accepted : 6 January 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009794, Breast Cancer Now;

Award ID: 2011MayPr35

Award Recipient : Stewart G. Martin

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer,msk,breast cancer-specific survival,biomarker

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer, msk, breast cancer-specific survival, biomarker

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High nuclear MSK1 is associated with longer survival in breast cancer patients

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Abstract

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Karger: Oncology

Most cited references 16

REporting recommendations for tumour MARKer prognostic studies (REMARK)

Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB.

High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses.

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Cited by 5

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