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Introduction Targeting PARP1 for synthetic lethality is a novel strategy for BRCA germ-line mutated breast cancers. However, BRCA germ-line mutations are rare and reactivation of BRCA mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting the more common sporadic breast cancers and pre-invasive ductal carcinoma in situ (DCIS) are desirable. Material and methods XRCC1 interacts with PARP1 and coordinates base excision repair. We investigated XRCC1- PARP1 expression in a large cohort of invasive breast cancers (n=1011 and pure DCIS (n=776). Pre-clinically, we monitored Olaparib effect on PARP1 and γH2AX cellular localisation by immunofluorescence. We investigated Olaparib sensitivity in a panel of XRCC1 proficient and deficient murine cell lines and human cancer cell lines. XRCC1 stable Knock out (KO) was generated by CRISPR-Cas9 system in invasive and DCIS model systems. We studied progression from epithelial to mesenchymal transition pheontype in XRCC1 deficient DCIS cells in a 3D culture model. Results and discussions Here we show that XRCC1 downregulation is an early event in human breast cancer pathogenesis. XRCC1 deficient DCIS are aggressive and associated with increased risk of local recurrence. XRCC1 deficient human invasive breast cancers with high PARP1 levels also manifest aggressive features and poor outcome. At cell line levels,we demonstrate that Olaparib (PARP1 inhibitor) is synthetically lethal in XRCC1 deficient DCIS and invasive breast cancer cells. Cell cycle response to Olaparib treatment in XRCC1 deficient cells was influenced by p53 pathway. In 3D-culture model, XRCC1 KO increased MCF10DCIS invasiveness and promoted epithelial to mesenchymal transition phenotype which was evident with their genetic signature profiling. Conclusion We conclude that PARP1 targeting is an attractive synthetic lethality and chemoprevention strategy in XRCC1 deficient breast cancers including pre-invasive DCIS.