Abstract
NF-small ka, CyrillicB has been linked to doxorubicin resistance in breast cancer patients. NF-small ka, CyrillicB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-small ka, CyrillicB-dependent genes and the biological consequences are unclear. We studied NF-small ka, CyrillicB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-small ka, CyrillicB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKbeta-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-small ka, CyrillicB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-small ka, CyrillicB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-small ka, CyrillicB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-small ka, CyrillicB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-small ka, CyrillicB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-small ka, CyrillicB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.
