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Targeting PARP1 in XRCC1 deficient sporadic invasive breast cancer or pre-invasive ductal carcinoma in situ induces synthetic lethality and chemoprevention

Ali, Reem; Al-kawaz, Abdulbaqi; Toss, Michael S; Green, Andrew R; Miligy, Islam M; Mesquita, Katia A.; Seedhouse, Claire; Mirza, Sameer; Band, Vimla; Rakha, Emad A; Madhusudan, Srinivasan

Authors

Reem Ali

Abdulbaqi Al-kawaz

Michael S Toss

Islam M Miligy

Katia A. Mesquita

Sameer Mirza

Vimla Band

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



Abstract

Targeting PARP1 for synthetic lethality is a new strategy for breast cancers harboring germline mutations in BRCA. However, these mutations are rare, and reactivation of BRCA-mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting more common sporadic breast cancers and pre-invasive ductal carcinoma in situ (DCIS) are desirable. Here we show that downregulation of XRCC1, which interacts with PARP1 and coordinates base excision repair, is an early event in human breast cancer pathogenesis. XRCC1-deficient DCIS were aggressive and associated with increased risk of local recurrence. Human invasive breast cancers deficient in XRCC1 and expressing high PARP1 levels also manifested aggressive features and poor outcome. The PARP1 inhibitor Olaparib was synthetically lethal in XRCC1-deficient DCIS and invasive breast cancer cells. We conclude that targeting PARP1 is an attractive strategy for synthetic lethality and chemoprevention in XRCC1-deficient breast cancers, including pre-invasive DCIS.

Journal Article Type Article
Publication Date Oct 8, 2018
Journal Cancer Research
Print ISSN 0008-5472
Electronic ISSN 1538-7445
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
APA6 Citation Ali, R., Al-kawaz, A., Toss, M. S., Green, A. R., Miligy, I. M., Mesquita, K. A., …Madhusudan, S. (2018). Targeting PARP1 in XRCC1 deficient sporadic invasive breast cancer or pre-invasive ductal carcinoma in situ induces synthetic lethality and chemoprevention. Cancer Research, doi:10.1158/0008-5472.can-18-0633
DOI https://doi.org/10.1158/0008-5472.can-18-0633
Keywords Cancer Research; Oncology

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