title: Activation of nuclear factor-kappa B is linked to resistance to neoadjuvant chemotherapy in breast cancer patients.
abstract: The nuclear factor (NF)-kappaB 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-kappaB in breast cancer, we aimed to study the value of basal NF-kappaB/p65 in predicting resistance to neoadjuvant chemotherapy, and to characterise the pharmacodynamic changes in NF-kappaB/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-kappaB/p65 subcellular expression. We studied NF-kappaB/p65, a well-characterised member of the NF-kappaB family that undergoes nuclear translocation when NF-kappaB is activated. Activation of NF-kappaB (i.e. nuclear NF-kappaB/p65 staining in pre-therapy specimens) was linked to chemoresistance. Patients with NF-kappaB/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-kappaB/p65 nuclear staining. Moreover, the number of patients with NF-kappaB/p65 activation increased after chemotherapy exposure. It is concluded that NF-kappaB/p65 activation assayed by immunohistochemistry is a predictive factor of resistance to neoadjuvant chemotherapy in breast cancer patients. Moreover, NF-kappaB activation was inducible following chemotherapy in a proportion of breast cancer patients. These novel clinical findings strengthen the rationale for the use of NF-kappaB inhibitors to prevent or overcome chemoresistance in breast cancer.
authors.affiliation: Medical Oncology Department, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona 08035, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Montagut
authors.forename: I
authors.initials: I
authors.lastname: Tusquets
authors.forename: B
authors.initials: B
authors.lastname: Ferrer
authors.forename: J M
authors.initials: JM
authors.lastname: Corominas
authors.forename: B
authors.initials: B
authors.lastname: Bellosillo
authors.forename: C
authors.initials: C
authors.lastname: Campas
authors.forename: M
authors.initials: M
authors.lastname: Suarez
authors.forename: X
authors.initials: X
authors.lastname: Fabregat
authors.forename: E
authors.initials: E
authors.lastname: Campo
authors.forename: P
authors.initials: P
authors.lastname: Gascon
authors.forename: S
authors.initials: S
authors.lastname: Serrano
authors.forename: P L
authors.initials: PL
authors.lastname: Fernandez
authors.forename: A
authors.initials: A
authors.lastname: Rovira
authors.forename: J
authors.initials: J
authors.lastname: Albanell
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D003593:Cytoplasm / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D020360:Neoadjuvant Therapy; D011379:Prognosis; D051996:Transcription Factor RelA / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018943:Anthracyclines; D016328:NF-kappa B; D051996:Transcription Factor RelA