Activation of nuclear factor-kappa B is linked to resistance to neloadjuvant chemotherapy in breast cancer patients

The nuclear factor (NF)-kappa B system is a promising anticancer target due to its role in oncogenesis and chemoresistance in preclinical models. To provide evidence in a clinical setting on the role of NF-kappa B in breast cancer, we aimed to study the value of basal NF-kappa B/p65 in predicting resistance to neoadjuvant chemotherapy, and to characterise the pharmacodynamic changes in NF-kappa B/p65 expression following chemotherapy in patients with locally advanced breast cancer. Pre- and post-chemotherapy tumour specimens from 51 breast cancer patients treated with anthracycline- and/or taxane-containing neoadjuvant chemotherapy were assayed by immunohistochemistry for NF-kappa B/p65 subcellular expression. We studied NF-kappa B/p65, a well-characterised member of the NF-kappa B family that undergoes nuclear translocation when NF-kappa B is activated. Activation of NF-kappa B (i.e. nuclear NF-kappa B/p65 staining in pre-therapy specimens) was linked to chemoresistance. Patients with NF-kappa B/p65 nuclear staining in pre-treatment samples had a 20% clinical response rate, while patients with undetected nuclear staining had a 91% response rate to chemotherapy (P = 0.002). Notably, four patients achieved a complete histological response and none of them had pre-treatment NF-kappa B/p65 nuclear staining. Moreover, the number of patients with NF-kappa B/p65 activation increased after chemotherapy exposure. It is concluded that NF-kappa B/p65 activation assayed by immunohistochemistry is a predictive factor of resistance to neoadjuvant chemotherapy in breast cancer patients. Moreover, NF-kappa B activation was inducible following chemotherapy in a proportion of breast cancer patients. These novel clinical findings strengthen the rationale for the use of NF-kappa B inhibitors to prevent or overcome chemoresistance in breast cancer.