Gene expression profiling of breast cancer cells in response to gemcitabine: NF-κB pathway activation as a potential mechanism of resistance

被引:0
作者
Héctor Hernández-Vargas
Socorro María Rodríguez-Pinilla
Mercedes Julián-Tendero
Pedro Sánchez-Rovira
Cristóbal Cuevas
Antonio Antón
Maria Jesus Ríos
José Palacios
Gema Moreno-Bueno
机构
[1] Spanish National Cancer Centre (CNIO),Breast and Gynaecological Cancer Group, Molecular Pathology Programme
[2] Complejo Hospitalario Ciudad de Jaén,Oncology Service
[3] Complejo Hospitalario,Pathology Service
[4] Ciudad de Jaén,Oncology Service
[5] Hospital Universitario Miguel Servet,Pathology Service
[6] Hospital Universitario Miguel Servet,undefined
[7] Spanish National Breast Cancer Research Group (GEICAM),undefined
[8] Group of Pathologists associated to GEICAM (pGEICAM),undefined
来源
Breast Cancer Research and Treatment | 2007年 / 102卷
关键词
Breast cancer; Gemcitabine; cDNA microarrays; NF-κB;
D O I
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学科分类号
摘要
Gemcitabine is a nucleoside analog with clinical relevance in the treatment of several solid tumors, including breast carcinoma. In spite of its cytotoxic effect, clinical efficacy is impaired by the development of resistance. We performed gene expression analysis to shed light into the molecular mechanism of action of this drug in two breast cancer cell lines. Activation of genes related with cell cycle, cell growth and apoptosis (BNIP3L, CCNG2, DDIT4, TGFB2, TP53BP1, TP53INP1, and VEGF) was the main finding in the p53-wild type cell line MCF7, while the p53-non-functional cell line MDA-MB-231 was characterized by the regulation of NF-κB target genes (BIRC3, CXCL1/GRO1, IRAK2, TNF, TNFAIP and TRAF1). Genes consistently induced (ATF3, CCNG2, CDKN1A, EGR1, INSIG1, and MAF) or repressed (CCND1 and VGF) in both cell lines, were also found after gemcitabine treatment. In addition, MDA-MB-231 cells showed a higher basal and induced NF-κB transcriptional activity after treatment with gemcitabine. In comparison with gemcitabine, gene expression after 5-fluorouracil treatment showed essentially different profiles in both cell lines. This, in spite of using equitoxic concentrations producing similar effects on cell cycle. NF-κB transcriptional activity in MDA-MB-231 cells was dependent on IκB-alpha phosphorylation, as shown by functional experiments using the specific inhibitor BAY11-7082. Moreover, immunohistochemical analysis of clinical samples of breast carcinoma further validated the induction of NF-κB expression and IκB down-regulation upon neoadjuvant gemcitabine treatment. Thus, gene expression patterns, in vitro functional studies and analysis of tissue samples are in agreement with a role for NF-κB pathway in gemcitabine response. Together with the reported role for NF-κB in the induction of resistance to chemotherapy, our data gives support to clinical strategies combining gemcitabine with NF-κB inhibitors in breast cancer.
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页码:157 / 172
页数:15
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