Role of IKKα andIKKα phosphorylation in patients with ER positive early-stage invasive breast cancer


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Phungern Khongthong1,Jean Quinn1,Lindsay Bennett2,Antonia Roseweir1,Joanne Edwards1
1University of Glasgow,2University of

Abstract

Background

Disease recurrence and endocrine resistance are still a major problem in oestrogen receptor (ER) positive breast cancer. The non-canonical NFκB pathway is one of the potential pathways, that may be involved in the development of endocrine resistance. The aim of this study was to examine the expression of IKKα and IKKα phosphorylation in ER-positive breast cancer tissue to assess associations with clinical outcome measures and endocrine resistance.

Method

Immunohistochemistry (IHC) for IKKα, IKKα phosphorylated at serine 176 (p-IKKαS176), threonine 23 (p-IKKαthr23) or tyrosine 423 (p-IKKαY463) was performed on a 392 patients tissue microarray (TMA) containing ER-positive breast cancers. Protein expression was assessed using the weighted histoscore (WHS) method and the median was employed as the cut off for low and high expression. The cohort was analysed for association with clinical features, cancer specific survival (CSS), recurrence free survival (RFS) and recurrence on tamoxifen (RoT).

Results

Within the full cohort, high cytoplasmic IKKα expression associated with an increasing Nottingham Prognostic index (p=0.019) and decreased CSS (p=0.012) RFS (p=0.028) and RoT (p=0.025).  These associations are potentiated in luminal B disease (CSS; p=0.024, RFS; p=0.031, RoT; p=0.029). However, high cytoplasmic p-IKKαS176 expression was associated with improved CSS (p=0.024), and this association is potentiated in luminal A disease (p=0.056). Similarly, high nuclear p-IKKαthr23 expression correlated with increasing grade (p=0.001) and Nottingham Prognostic Index (p=0.031) and was associated with decreased CSS (p=0.023) and RoT (p=0.026) for the and these associations were potentiated in luminal A disease (CSS; p=0.010, RoT p=0.009). No associations were observed for p-IKKαY463and clinical outcome measures.

Conclusion

IKKα associates with poor prognosis in patients with ER-positive breast cancer. Interestingly, this appears to be driven by phosphorylation at T23 (the AKT site) rather than S176 (the classical NIK site). Therefore, combine IKKα and AKT inhibition may help overcome endocrine resistance in these patients.