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Cited by 47Bone health and treatmentsBreast Cancer Treatment StudiesMechanisms of cancer metastasis

Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer

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Westbrook, Jules A, Wood, Steven L, Cairns, David A, McMahon, Kathryn, Gahlaut, Renu, Thygesen, Helene, Shires, Mike, Roberts, Stephanie +9 more·2019·The Journal of Pathology
DOI 10.1002/path.5197PMC PMC6618075
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Abstract

Skeletal metastasis occurs in around 75% of advanced breast cancers, with the disease incurable once cancer cells disseminate to bone, but there remains an unmet need for biomarkers to identify patients at high risk of bone recurrence. This study aimed to identify such a biomarker and to assess its utility in predicting response to adjuvant zoledronic acid (zoledronate). We used quantitative proteomics (stable isotope labelling by amino acids in cell culture-mass spectrometry; SILAC-MS) to compare protein expression in a bone-homing variant (BM1) of the human breast cancer cell line MDA-MB-231 with parental non-bone-homing cells to identify novel biomarkers for risk of subsequent bone metastasis in early breast cancer. SILAC-MS showed that dedicator of cytokinesis protein 4 (DOCK4) was upregulated in bone-homing BM1 cells, confirmed by western blotting. BM1 cells also had enhanced invasive ability compared with parental cells, which could be reduced by DOCK4-shRNA. In a training tissue microarray (TMA) comprising 345 patients with early breast cancer, immunohistochemistry followed by Cox regression revealed that high DOCK4 expression correlated with histological grade (p = 0.004) but not oestrogen receptor status (p = 0.19) or lymph node involvement (p = 0.15). A clinical validation TMA used tissue samples and the clinical database from the large AZURE adjuvant study (n = 689). Adjusted Cox regression analyses showed that high DOCK4 expression in the control arm (no zoledronate) was significantly prognostic for first recurrence in bone (HR 2.13, 95%CI 1.06-4.30, p = 0.034). No corresponding association was found in patients who received zoledronate (HR 0.812, 95%CI 0.176-3.76, p = 0.790), suggesting that treatment with zoledronate may counteract the higher risk for bone relapse from high DOCK4-expressing tumours. High DOCK4 expression was not associated with metastasis to non-skeletal sites when these were assessed collectively. In conclusion, high DOCK4 in early breast cancer is significantly associated with aggressive disease and with future bone metastasis and is a potentially useful biomarker for subsequent bone metastasis risk. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Authors
Westbrook, J. A., Wood, S. L., Cairns, D. A., McMahon, K., Gahlaut, R., Thygesen, H., Shires, M., Roberts, S., Marshall, H., Oliva, M. R., Dunning, M. J., Hanby, A. M., Selby, P. J., Speirs, V., Mavria, G., Coleman, R. E., & Brown, J. E.
Affiliations
  • University of Leeds (GB)
  • University of Sheffield (GB)
Corresponding author
Brown, Janet E
ORCID
Venue
The Journal of Pathology
Publisher
Wiley
Published
2019-01-25
Volume
247
Issue
3
Pages
381-391
ISSN
  • 0022-3417 (ISSN-L)
  • 1096-9896
DOI
10.1002/path.5197
PMC
PMC6618075
OpenAlex
W2900926148
Cited by
47
References
4
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 7 · 2020: 11 · 2019: 6
FWCI
2.26
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Pathology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
Funders
  • Cancer Research UK (C18605/A 10048)
  • Yorkshire Cancer Research (S315)
  • Breast Cancer Now (2012MaySP047, 2016MayPR74)
Topics
  • Health Sciences › Medicine › Oncology › Bone health and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
DOCK4, bone metastasis, early breast cancer, prognostic factors, zoledronic acid, MDA-MB-231 cells, tumor invasion, histological grade, adjuvant therapy response, osteoclasts
MeSH terms
Zoledronic Acid, Adult, Aged, Aged, 80 and over, Bone Neoplasms, Breast Neoplasms, Cell Movement, Female, Humans, Middle Aged, Neoplasm Proteins, Prognosis, Tumor Cells, Cultured, Biomarkers, Tumor, Up-Regulation, Chemotherapy, Adjuvant, Risk Assessment, GTPase-Activating Proteins, Proteomics, Cell Line, Tumor, Bone Density Conservation Agents, Gene Knockdown Techniques, Young Adult, Neoplasm Grading

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