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Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-?B target genes in human breast cancer.

ABSTRACT: NF-?B has been linked to doxorubicin resistance in breast cancer patients. NF-?B nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-?B-dependent genes and the biological consequences are unclear. We studied NF-?B-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-?B-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKK?-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-?B 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-?B 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-?B-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-?B driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-?B/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-?B-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.

SUBMITTER: Dalmases A

PROVIDER: S-EPMC3960201 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.

Dalmases Alba A González Irene I Menendez Silvia S Arpí Oriol O Corominas Josep Maria JM Servitja Sonia S Tusquets Ignasi I Chamizo Cristina C Rincón Raúl R Espinosa Lluis L Bigas Anna A Eroles Pilar P Furriol Jessica J Lluch Anna A Rovira Ana A Albanell Joan J Rojo Federico F

Oncotarget 20140101 1

NF-кB has been linked to doxorubicin resistance in breast cancer patients. NF-кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB-dependent genes and the biological consequences are unclear. We studied NF-кB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 ...[more]

PMID: 24344116

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Project description:BackgroundNuclear factor ?B (NF-?B)-mediated pathways have been widely implicated in cell survival, development and tumor progression. Although the molecular events of determining NF-?B translocation from cytoplasm to nucleus have been extensively documented, the regulatory mechanisms of NF-?B activity inside the nucleus are still poorly understood. Being a special member of macro domain proteins, LRP16 was previously identified as a coactivator of both estrogen receptor and androgen receptor, and as an interactor of NF-?B coactivator UXT. Here, we investigated the regulatory role of LRP16 on NF-?B activation.MethodologyGST pull-down and coimmunoprecipitation (CoIP) assays assessed protein-protein interactions. The functional activity of NF-?B was assessed by luciferase assays, changes in expression of its target genes, and its DNA binding ability. Annexin V staining and flow cytometry analysis were used to evaluate cell apoptosis. Immunohistochemical staining of LRP16 and enzyme-linked immunosorbent assay-based evaluation of active NF-?B were performed on primary human gastric carcinoma samples.ResultsWe demonstrate that LRP16 integrates into NF-?B transcriptional complex through associating with its p65 component. RNA interference knockdown of the endogenous LRP16 in cells leads to impaired NF-?B activity and significantly attenuated NF-?B-dependent gene expression. Mechanistic analysis revealed that knockdown of LRP16 did not affect tumor necrosis factor ? (TNF-?)-induced nuclear translocation of NF-?B, but blunted the formation or stabilization of functional NF-?B/p300/CREB-binding protein transcription complex in the nucleus. In addition, knockdown of LRP16 also sensitizes cells to apoptosis induced by TNF-?. Finally, a positive link between LRP16 expression intensity in nuclei of tumor cells and NF-?B activity was preliminarily established in human gastric carcinoma specimens.ConclusionsOur findings not only indicate that LRP16 is a crucial regulator for NF-?B activation inside the nucleus, but also suggest that LRP16 may be an important contributor to the aberrant activation of NF-?B in tumors.

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Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-?B target genes in human breast cancer.

Publications

Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.

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