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

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

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)6818-6827
Number of pages10
JournalCancer Research
Volume78
Issue number24
DOIs
StatePublished - Dec 15 2018

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Carcinoma, Intraductal, Noninfiltrating
Carcinoma in Situ
Chemoprevention
Breast Neoplasms
Germ-Line Mutation
DNA Repair
Synthetic Lethal Mutations
Down-Regulation
Recurrence
Mutation
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting PARP1 in XRCC1-deficient sporadic invasive breast cancer or preinvasive 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.

In: Cancer Research, Vol. 78, No. 24, 15.12.2018, p. 6818-6827.

Research output: Contribution to journalArticle

Ali, R, Al-Kawaz, A, Toss, MS, Green, AR, Miligy, IM, Mesquita, KA, Seedhouse, C, Mirza, S, Band, V, Rakha, EA & Madhusudan, S 2018, 'Targeting PARP1 in XRCC1-deficient sporadic invasive breast cancer or preinvasive ductal carcinoma in situ induces synthetic lethality and chemoprevention', Cancer Research, vol. 78, no. 24, pp. 6818-6827. https://doi.org/10.1158/0008-5472.CAN-18-0633
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. / Targeting PARP1 in XRCC1-deficient sporadic invasive breast cancer or preinvasive ductal carcinoma in situ induces synthetic lethality and chemoprevention. In: Cancer Research. 2018 ; Vol. 78, No. 24. pp. 6818-6827.
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