Westbrook, JA, Wood, SL, Cairns, DA orcid.org/0000-0002-2338-0179 et al. (14 more authors) (2019) Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer. The Journal of pathology, 247 (3). pp. 381-391. ISSN 0022-3417
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. We used quantitative proteomics (SILAC-MS), to compare protein expression in a bone-homed 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 zoledronic acid) 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 zoledronic acid (HR 0.812, 95%CI 0.176-3.76, p=0.790), suggesting that treatment with zoledronic acid 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This article is protected by copyright. All rights reserved. This is the peer reviewed version of the following article: Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer, which has been published in final form at https://doi.org/10.1002/path.5197. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
Keywords: | DOCK4; bone metastasis; breast cancer; biomarker; proteomics |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Biomarkers and Therapy (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Pathology & Tumour Biology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Clinical Trials Research (LICTR) (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > School of Medicine - Dean's Office (Leeds) |
Funding Information: | Funder Grant number MRC G0802416 |
Depositing User: | Symplectic Publications |
Date Deposited: | 07 Dec 2018 13:21 |
Last Modified: | 29 Jun 2020 13:35 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/path.5197 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:139640 |