ArrayExpress Uploader0humanSKR6LR cells, which are SKR6 cells that were treated with increasing lapatinib concentrations (0.2 to 5 μM) for several months to derive a resistant cell population.SKR6LR cells, which are SKR6 cells that were treated with increasing lapatinib concentrations (0.2 to 5 μM) for several months to derive a resistant cell population.SKR6LR cells, which are SKR6 cells that were treated with increasing lapatinib concentrations (0.2 to 5 μM) for several months to derive a resistant cell population.SKR6CA cells, which are SKR6 cells that were retrovirally transduced with constitutively active NF-κB relA/p65 (CAp65) and selected with puromycinSKR6CA cells, which are SKR6 cells that were retrovirally transduced with constitutively active NF-κB relA/p65 (CAp65) and selected with puromycinSKR6CA cells, which are SKR6 cells that were retrovirally transduced with constitutively active NF-κB relA/p65 (CAp65) and selected with puromycinSKR6-Vector cells, which are SKR6 cells that were retrovirally transduced with the pQCXIP empty retroviral vector and selected with puromycinSKR6-Vector cells, which are SKR6 cells that were retrovirally transduced with the pQCXIP empty retroviral vector and selected with puromycinSKR6-Vector cells, which are SKR6 cells that were retrovirally transduced with the pQCXIP empty retroviral vector and selected with puromycinSKBR-3 cell population with elevated HER2 expressionSKBR-3 cell population with elevated HER2 expressionSKBR-3 cell population with elevated HER2 expression2124arrayexpress_sid4Breast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are...E-GEOD-52707/profile/8773/arrayexpressuploader112breastbreast cancercancercellcentralDec.12, 2014Falsenuclear-factor-kappa-b-activation-induced-anti-apoE-GEOD-52707_A-AFFY-44Nuclear factor kappa B activation-induced anti-apoptosis renders HER2 positive cells drug resistant and accelerates tumor growthJul.11, 2014Breast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are initially effective against HER2- positive breast cancer, but resistance inevitably occurs. We previously found that nuclear factor kappa B is hyper-activated in the subset of HER-2 positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-κB rendered HER2-positive cancer cells resistant to anti-HER2 drugs, and cells selected for Lapatinib resistance up-regulated NF-κB. In both circumstances, cells were anti-apoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-κB inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NF-κB-responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-κB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-κB activation, and selection for resistance results in NF-κB activation, suggesting this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-κB suggests a potential treatment paradigm for patients who relapse after anti-HER2 therapy. Patients with these cancers may be treated by simultaneously suppressing HER2 signaling and NF-κB activation. We used microarrays to detail the gene expression differences underlying the characterictic survival differences between the SKR6, SKR6-Vector, SKR6CA, and SKR6LR cell lines, which are defined as follows: SKR6: A clonal derivative of SKBR3 cells isolated by fluorescence-activated cell sorting (FACS) to enrich for elevated HER2 levels, SKR6CA: SKR6 cells retrovirally transduced with constitutively active NF-κB relA/p65 (CAp65) and selected with puromycin, SKR6 vector: SKR6 cells transduced with the pQCXIP empty retroviral vector and selected with puromycin, and SKR6LR: SKR6 cells treated with increasing lapatinib concentrations (0.2 to 5 μM) for several months. We sorted SKBR-3 cells by fluorescence-activated cell sorting (FACS) to enriched for cell population with elevated HER2 expression, which we termed SKR6. The following cell lines were then created from SKR6 cells: SKR6CA: SKR6 cells retrovirally transduced with constitutively active NF-κB relA/p65 (CAp65), SKR6 vector: SKR6 cells transduced with the pQCXIP empty retroviral vector and selected with puromycin, and SKR6LR: SKR6 cells treated with increasing lapatinib concentrations (0.2 to 5 μM) for several months.http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-52707http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-52707/samples/