Activation of nuclear factor-κ B is linked to resistance to neoadjuvant chemotherapy in breast cancer patients

Abstract

The nuclear factor (NF)-kB 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-kB in breast cancer, we aimed to study the value of basal NF-kB/p65 in predicting resistance to neoadjuvant chemotherapy, and to characterise the pharmacodynamic changes in NF-kB/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-kB/p65 subcellular expression. We studied NF-kB/p65, a wellcharacterised member of the NF-kB family that undergoes nuclear translocation when NF-kB is activated. Activation of NF-kB (i.e. nuclear NF-kB/p65 staining in pre-therapy specimens) was linked to chemoresistance. Patients with NF-kB/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 ¼ 0.002). Notably, four patients achieved a complete histological response and none of them had pre-treatment NF-kB/p65 nuclear staining. Moreover, the number of patients with NF-kB/p65 activation increased after chemotherapy exposure. It is concluded that NF-kB/p65 activation assayed by immunohistochemistry is a predictive factor of resistance to neoadjuvant chemotherapy in breast cancer patients. Moreover, NF-kB activation was inducible following chemotherapy in a proportion of breast cancer patients. These novel clinical findings strengthen the rationale for the use of NF-kB inhibitors to prevent or overcome chemoresistance in breast cancer.

Strong cytoplasmic expression of NF-κB/p65 correlates with a good prognosis in patients with triple-negative breast cancer

“…Previous studies demonstrated that nuclear NF-κB/p65 staining in pre-treatment samples was linked to resistance to neoadjuvant chemotherapy [13,14]. In contrast, Jones and colleagues reported that nuclear NF-κB/p65 staining was associated with high histological grade, ER negativity and higher grade, and that patients with nuclear NF-κB/p65 staining had a higher pCR rate than those without [15].…”

“…It has been shown that constitutive NF-κB activity is detected in breast cancer cell lines, and is preferentially involved in the proliferation of the basal-like (triple-negative) subtype [12]. Previous studies showed that nuclear NF-κB/p65 expression was a predictive factor of resistance to neoadjuvant chemotherapy in breast cancer [13,14]. In contrast, a recent study demonstrated that nuclear NF-κB/p65 expression was associated with high histological grade, ER negativity, higher Ki67 index and increased pCR after neoadjuvant chemotherapy [15].…”

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

“…Although the molecular basis of resistance to Taxol is not well-documented, mounting evidence supports the role of intrinsically or constitutively activated nuclear factor-κB (NF-κB) in affording protection against programmed cell death. Constitutive high levels of NF-κB activity have been detected in response to chemotherapy and radiation in ovarian cancer (3)(4)(5), pancreatic cancer (6), breast cancer (7,8), and prostate cancer (9). Our recent work has revealed that nuclear RelA and cytoplasmic pI-κBα are significantly associated with a poor prognosis in cancer (10).…”

Curcumin potentiates the effect of chemotherapy against acute lymphoblastic leukemia cells via downregulation of NF-κB

“…The REH cell line (St. Jude Children's Research Hospital, Memphis, TN, USA) was cultured in RMPI-1640 medium supplemented with 100 U/ml penicillin and 100 g/ml streptomycin with 10% FBS in a humidified incubator at 37˚C with an atmosphere of 5% CO 2 . Next, 5x10 5 REH cells were treated for 48 h in triplicate with 125 µg/ml prednisone, 250 µg/ml 6-mercaptopurine, 0.4 µg/ml dexamethasone, 50 µg/ml cyclophosphamide, 5 U l-asparaginase, 25 µg/ml vincristine, 1 µg/ml daunorubicin, 0.5 µg/ml doxorubicin, 7.5 µg/ml methotrexate and 1.25 µg/ml cytarabine, with or without 20 µM curcumin. Untreated cells served as the control group.…”

“…The pathogenesis of ALL includes changes in gene expression, which are regulated by diverse transcription factors (3) such as nuclear factor-kappa B (NF-κB), which has been associated with cell proliferation and survival (4). Additionally, in solid tumors, NF-κB exhibits an important function in invasion, angiogenesis, aggressive tumor growth and chemoresistance (4)(5)(6). Constitutive activation of NF-κB is observed in ~92% of pediatric ALL patients (7) and thus is one of the targets for chemosensitization.…”