A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer
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Niamh E. Buckley1, Paula Haddock1, Ricardo De Matos Simoes1, Eileen Parkes1, Gareth Irwin1, Frank Emmert-Streib1, Stephen McQuaid1, Richard Kennedy1 and Paul Mullan1
1 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK
Niamh E. Buckley, email:
Keywords: triple negative breast cancer; BRCA1; NFkB; predictive biomarker; microenvironment
Received: February 11, 2016 Accepted: February 18, 2016 Published: March 02, 2016
Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or ‘BRCAness’, is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies.
We have discovered a consistent NFκB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFκB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFκB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour-derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways.
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