TI - Gene expression profiling of breast cancer cells in response to gemcitabine : NF-kappaB pathway activation as a potential mechanism of resistance . AB - 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-kappaB 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-kappaB 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-kappaB transcriptional activity in MDA-MB-231 cells was dependent on IkappaB-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-kappaB expression and IkappaB 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-kappaB pathway in gemcitabine response . Together with the reported role for NF-kappaB in the induction of resistance to chemotherapy , our data gives support to clinical strategies combining gemcitabine with NF-kappaB inhibitors in breast cancer .