Abstract 3468: NF-κB pathways are associated with increased recurrence in different subtypes of ER positive breast cancer.
Authors: Lindsay Bennett, Clare Orange, Elizabeth Mallon, Julie Doughty, Paul G. Horgan, Andrew Paul, Joanne Edwards
Journal: Cancer Research (2013)

Abstract Although therapies exist for breast cancer and mortality rates have fallen, resistance to current therapies remains a major problem. The NF-κB pathways regulate the transcription of a wide range of genes involved in the immune response, inflammation, proliferation and apoptosis. Many of these processes are hallmarks of cancer and NF-κB has been hypothesised to be a link between inflammation and tumourigenesis. The aim of the current study was to investigate the role of both NF-κB pathways in the pathogenesis and recurrence of breast cancer. Immunohistochemistry was employed to assess key components of the canonical (p65 and IKKβ) and non-canonical (NIK, RelB, IKKα) pathways on a TMA of 544 patients with full clinical follow up and clinical information including ER status, subtype (luminal A/B, triple negative, HER2 enriched), necrosis, apoptosis and angiogenesis. Nuclear expression of p-p65 S536 was observed in 81% (336/414) of patients and was associated with angiogenesis (p=0.028) and disease free survival (p=0.003). Those patients with tumours that expressed high levels of p-p65 S536 in the nuclear compartment had significantly shorter disease free survival compared to those with low expression (6.95 years vrs 7.91 years). The cohort was then subdivided by ER status and this observation was attenuated in ER positive tumours (p=0.002, 7.10 years vrs 8.34 years). When split further into subtype this was negated in luminal A tumours (p=0.120) but significance increased in luminal B tumours (p=2.54x10-4, 5.52 years vrs 8.16 years). A differing role was observed for the non-canonical pathway. Cytoplasmic expression of IKKα was observed in 97% (367/378) of patients and was associated with apoptosis (p=0.024) and necrosis (p=0.020) and a shorter disease free survival in those with high expression (p=0.014, 7.16 years vrs 7.64 years). This observation was attenuated in ER positive tumours when the cohort was subdivided by ER status (p=0.008, 7.56 years vrs 8.00 years). When split into subtype, the relationship between cytoplasmic IKKα and disease free survival was negated in all subtypes except luminal A (p=0.015, 7.92 years vrs 8.32 years). Other members of the NF-κB pathways (p65 NLS, IKKβ, NIK and RelB) were not associated with disease free survival. Our results suggest that the NF-κB pathways are involved in promoting recurrence in patients with ER positive tumours and may be involved with development of endocrine resistance. However, each pathway seems to be involved in different subtypes with the canonical pathway associating with recurrence in the luminal B subtype and the non-canonical with the luminal A subtype. Further studies in an independent cohort combined with mechanistic studies are required. These results highlight that patients with ER positive tumours may have different signalling pathways driving recurrence and therefore benefit from different therapeutic strategies. Citation Format: Lindsay Bennett, Clare Orange, Elizabeth Mallon, Julie Doughty, Paul G. Horgan, Andrew Paul, Joanne Edwards. NF-κB pathways are associated with increased recurrence in different subtypes of ER positive breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3468. doi:10.1158/1538-7445.AM2013-3468