A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer.

Niamh E Buckley,Gareth Irwin,Paul Mullan,Paula Haddock,Stephen Mcquaid,Frank Emmert-Streib,Eileen Parkes,Richard Kennedy,Ricardo De Matos Simoes

doi:10.18632/oncotarget.7865

Abstract

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.

Highlights

Breast cancer is a heterogeneous disease comprising of multiple tumour types that require different treatment approaches and have varied patient outcomes
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
Using a NFκB luciferase reporter assay, higher NFκB activity is observed in BRCA1 mutant HCC1937 (Figure 1A(i)) and BRCA1 low MDA-MB-468 (Figure 1A(ii)) cells compared to their isogenic matched BRCA1 reconstituted controls

Summary

Introduction

Breast cancer is a heterogeneous disease comprising of multiple tumour types that require different treatment approaches and have varied patient outcomes. Patient stratification, based on expression of the estrogen (ERα) or Her2/neu/ERBB2 (Her2) receptors, has allowed for the use of targeted therapies such as Tamoxifen and Trastuzamab, respectively. All TNBCs are currently treated with DNA-damaging chemotherapy regimes such as FEC (5-FU, Epirubucin and Cyclophosphamide). They are a poorly defined subgroup with a large degree of heterogeneity suggesting that optimal treatment may only be attained by use of different treatment regimens. Gene expression microarray analyses of tumours has allowed breast cancers to be re-classified. These include the ERα and Her positive subgroups in addition to a Basal-like (BLBC) subgroup which is associated with the poorest clinical outcomes [1]. There is a high degree of overlap between the TNBC and BLBC subgroups with up to 70% of TNBCs displaying BLBC gene profiles as well as 77% of BLBCs classified as TNBC [2]

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