title: Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.
abstract: 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 status. NF-кB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKβ-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-кB 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-кB 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-кB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-кB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-кB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-кB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Dalmases
authors.forename: Irene
authors.initials: I
authors.lastname: González
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Oriol
authors.initials: O
authors.lastname: Arpí
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Corominas
authors.forename: Sonia
authors.initials: S
authors.lastname: Servitja
authors.forename: Ignasi
authors.initials: I
authors.lastname: Tusquets
authors.forename: Cristina
authors.initials: C
authors.lastname: Chamizo
authors.forename: Raúl
authors.initials: R
authors.lastname: Rincón
authors.forename: Lluis
authors.initials: L
authors.lastname: Espinosa
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.forename: Pilar
authors.initials: P
authors.lastname: Eroles
authors.forename: Jessica
authors.initials: J
authors.lastname: Furriol
authors.forename: Anna
authors.initials: A
authors.lastname: Lluch
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin