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The frequency and clinical significance of DNA polymerase beta (POLβ) expression in breast ductal carcinoma in situ (DCIS)

Al-Kawaz, Abdulbaqi; Ali, Reem; Toss, Michael S.; Miligy, Islam M.; Mohammed, Omar J.; Green, Andrew R.; Madhusudan, Srinivasan; Rakha, Emad A.

The frequency and clinical significance of DNA polymerase beta (POLβ) expression in breast ductal carcinoma in situ (DCIS) Thumbnail


Authors

Abdulbaqi Al-Kawaz

Reem Ali

Michael S. Toss

Islam M. Miligy

Omar J. Mohammed

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology



Abstract

Background: The prediction of clinical behaviour of breast ductal carcinoma in situ (DCIS) and its progression to invasive disease remains a challenge. Alterations of DNA damage repair mechanisms are associated with invasive breast cancer (BC). This study aims to assess the role of base excision repair (BER) DNA Polymerase Beta (POLβ) in DCIS. Methods: A cohort of DCIS comprising pure DCIS (n = 776) and DCIS coexisting with invasive BC (n = 239) were prepared as tissue microarrays. POLβ protein expression was assessed using immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Preclinically, we investigated the impact of POLβ depletion on stem cell markers in representative DCIS cell line models. Results: Reduced POLβ expression was associated with aggressive DCIS features including high nuclear grade, comedo necrosis, larger tumour size, hormonal receptor negativity, HER2 overexpression and high Ki67 index. Combined low nuclear/low cytoplasmic POLβ expression showed the strongest association with the features’ characteristics of aggressive behaviour. There was a gradual reduction in the POLβ expression from normal breast tissue, to DCIS, with the lowest expression observed in the invasive BC. Low POLβ expression was an independent predictor of recurrence in DCIS patients treated with breast conserving surgery (BCS). POLβ knockdown was associated with a significant increase in cell stemness markers including SOX2, NANOG and OCT4 levels in MCF10-DCIS cell lines. Conclusion: Loss of POLβ in DCIS is associated with aggressive behaviour and it can predict recurrence. POLβ expression in DCIS provides an additional feature for patients’ risk stratification for personalised therapy.

Citation

Al-Kawaz, A., Ali, R., Toss, M. S., Miligy, I. M., Mohammed, O. J., Green, A. R., …Rakha, E. A. (2021). The frequency and clinical significance of DNA polymerase beta (POLβ) expression in breast ductal carcinoma in situ (DCIS). Breast Cancer Research and Treatment, 190, 39-51. https://doi.org/10.1007/s10549-021-06357-7

Journal Article Type Article
Acceptance Date Aug 6, 2021
Online Publication Date Aug 18, 2021
Publication Date Nov 1, 2021
Deposit Date Aug 25, 2021
Publicly Available Date Aug 27, 2021
Journal Breast Cancer Research and Treatment
Print ISSN 0167-6806
Electronic ISSN 1573-7217
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 190
Pages 39-51
DOI https://doi.org/10.1007/s10549-021-06357-7
Keywords Cancer Research; Oncology
Public URL https://nottingham-repository.worktribe.com/output/6091683
Publisher URL https://link.springer.com/article/10.1007%2Fs10549-021-06357-7

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