Deficiency in tumor suppressor p53 is required for doxorubicin induced transcriptional upregulation of NF-kB target genes in human breast cancer

ABSTRACT: NF-kB has been linked to doxorubicin-based chemotherapy resistance in breast cancer patients. NF-kB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined, however its functional consequences in terms the spectrum of NF-kB -dependent genes expressed and, thus, the impact on tumour cell behaviour are unclear. We hypothesized that NF-kB gene expression profile induced by doxorubicin might be different among breast cancer cells and tumors. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-kB driven-gene transcription demonstrated by gene expression microarrays. Selected genes (ICAM-1, CXCL1, IL8) related with invasion, metastasis and chemoresistance expression were confirmed by RT-PCR in a subset of additional doxorubicin-treated cells and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of these NF-kB targeted genes. Overexpression of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-kB driven transcription induced by doxorubicin. Moreover, tumors with a p53 deficient background and nuclear NF-kB /p65 expression correlated with reduced disease free-survival. This study supports that tumor molecular profiles for doxorubicin driven NF-kB-response are likely to exist. A link between p53 deficiency and the presence of active transcriptionally NF-kB could favour an aggressive behaviour and might have implications for doxorubicin-based chemotherapy in breast tumors exhibiting aberrant p53 activity 12 samples were analyzed: controls (n=3); Doxorubicin treated (n=3); MLN120B treated (n=3); MLN120B + Doxorubicin treated (n=3)

ORGANISM(S): Homo sapiens

SUBMITTER: Dalmases Alba 

PROVIDER: S-ECPF-GEOD-47013 | biostudies-other |

REPOSITORIES: biostudies-other