Montagut C, Tusquets I, Ferrer B, Corominas J M, Bellosillo B, Campas C, Suarez M, Fabregat X, Campo E, Gascon P, Serrano S, Fernandez P L, Rovira A, Albanell J
Medical Oncology Department, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona 08035, Spain.
Endocr Relat Cancer. 2006 Jun;13(2):607-16. doi: 10.1677/erc.1.01171.
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.
核因子（NF）-κB系统因其在临床前模型的肿瘤发生和化疗耐药中的作用，是一个很有前景的抗癌靶点。为了在临床环境中提供关于NF-κB在乳腺癌中作用的证据，我们旨在研究基础NF-κB/p65在预测新辅助化疗耐药性方面的价值，并描述局部晚期乳腺癌患者化疗后NF-κB/p65表达的药效学变化。对51例接受含蒽环类和/或紫杉烷类新辅助化疗的乳腺癌患者化疗前后的肿瘤标本进行免疫组织化学检测，以分析NF-κB/p65的亚细胞表达。我们研究的NF-κB/p65是NF-κB家族中一个特征明确的成员，当NF-κB被激活时，它会发生核转位。NF-κB的激活（即治疗前标本中的核NF-κB/p65染色）与化疗耐药相关。治疗前样本中NF-κB/p65核染色的患者临床缓解率为20%，而未检测到核染色的患者化疗缓解率为91%（P = 0.002）。值得注意的是，有4例患者达到了完全组织学缓解，且他们均无治疗前NF-κB/p65核染色。此外，化疗后NF-κB/p65激活的患者数量增加。结论是，通过免疫组织化学检测的NF-κB/p65激活是乳腺癌患者新辅助化疗耐药的预测因素。此外，一部分乳腺癌患者化疗后可诱导NF-κB激活。这些新的临床发现强化了使用NF-κB抑制剂预防或克服乳腺癌化疗耐药的理论依据。
