Targeting PARP1 in XRCC1-Deficient Sporadic Invasive Breast Cancer or Preinvasive Ductal Carcinoma In Situ Induces Synthetic Lethality and Chemoprevention
| Autor: | Emad A. Rakha, Reem Ali, Katia A. Mesquita, Srinivasan Madhusudan, Sameer Mirza, Islam M. Miligy, Abdulbaqi AlKawaz, Michael S. Toss, Andrew R. Green, Vimla Band, Claire Seedhouse |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Nottingham Breast Cancer Research Centre business.industry Synthetic lethality Ductal carcinoma medicine.disease Olaparib 03 medical and health sciences chemistry.chemical_compound XRCC1 030104 developmental biology Breast cancer Germline mutation Oncology chemistry Carcinoma Cancer research Medicine skin and connective tissue diseases business Synthetic Lethal Mutations |
| Zdroj: | Cancer Research. 78:6818-6827 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-18-0633 |
| Popis: | 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 preinvasive 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 preinvasive DCIS. Significance: These findings show that loss of XRCC1, which is associated with more malignant DCIS, can be exploited by PARP inhibition, suggesting its application as a promising therapeutic and chemoprevention strategy in XRCC1-deficient tumor cells. |
| Databáze: | OpenAIRE |
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