Constitutive activation of nuclear factor‐κB is preferentially involved in the proliferation of basal‐like subtype breast cancer cell lines

Abstract

Constitutive nuclear factor (NF)-kB activation is thought to be involved in survival, invasion, and metastasis in various types of cancers. However, neither the subtypes of breast cancer cells with constitutive NF-kB activation nor the molecular mechanisms leading to its constitutive activation have been clearly defined. Here, we quantitatively analyzed basal NF-kB activity in 35 human breast cancer cell lines and found that most of the cell lines with high constitutive NF-kB activation were categorized in the estrogen receptor negative, progesterone receptor negative, ERBB2 negative basal-like subtype, which is the most malignant form of breast cancer. B reast cancer is a disease of the mammary epithelium, which is composed of two major types of differentiated cells: luminal epithelial cells and basal or myoepithelial cells.(1) Recent studies have identified self-renewing pluripotent stem cells in mammary epithelium and suggest a model in which these stem cells could differentiate into the luminal-or basal-restricted lineages. Molecular taxonomic analyses of breast cancers by gene expression profiling have identified five breast cancer subtypes: luminal A, luminal B, basal-like, ERBB2-positive, and normal breast-like.(2) This classification is closely associated with the differentiation model of mammary epithelium. Luminal-and basallike breast cancer subtypes express genes characteristic of the two distinct types of epithelial cells. These subtypes show different clinical courses and responses to therapeutic agents. The basallike subtype has been associated with aggressive behavior and poor prognosis and typically does not express estrogen receptor (ER), progesterone receptor (PR), or ERBB2 ("triple-negative" phenotype).(3) Therefore, patients with basal-like subtype are unlikely to benefit from currently available targeted therapeutic strategies, such as hormone therapy and Herceptin (Roche, Basel, Switzerland). It is thus crucial to identify effective molecular targets for this subtype of breast cancer.Nuclear factor (NF)-κB transcription factors are important regulators of the genes necessary for innate and adaptive immune responses and for the survival and proliferation of certain cell types. The NF-κB family is composed of five different proteins, including RelA, RelB, c-Rel, and the precursor and processed products of the NFKB1 (p105/p50) and NFKB2 (p100/p52) genes.These proteins homodimerize and/or heterodimerize to form active transcription factors. Two distinct NF-κB pathways have been proposed: the classical pathway, which activates the RelA-p50 complex, and the alternative pathway, which activates the RelBp52 complex.(4) In normal cells, activation of the classical and alternative pathways is tightly regulated by inhibitor of NF-κB (IκB) family proteins and a p100 protein, respectively. Both NF-κB pathways are aberrantly activated and involved in tumor development in various cancers, including breast cancer.(5,6) Previous studies have revealed that hormone-independent breast cancer cells exhibit cons...

Triple-Negative Subtype Predicts Poor Overall Survival and High Locoregional Relapse in Inflammatory Breast Cancer

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Tropomodulin 1 Expression Driven by NF-κB Enhances Breast Cancer Growth

“…The preparation of recombinant adenoviruses was performed as described previously (11). RNA samples were prepared from MDA-MB-436 cells 24 hours after infections.…”

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

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