Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.
Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.
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DOI：
10.18632/oncotarget.1556
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发表时间：
2014-01-15
期刊：
影响因子：
--
通讯作者：
Rojo F
中科院分区：
文献类型：
--
作者：
Dalmases A;González I;Menendez S;Arpí O;Corominas JM;Servitja S;Tusquets I;Chamizo C;Rincón R;Espinosa L;Bigas A;Eroles P;Furriol J;Lluch A;Rovira A;Albanell J;Rojo F
NF-κB与乳腺癌患者的阿霉素耐药有关。多柔比星处理的乳腺癌细胞中NF-κB核转位和DNA结合已被广泛研究，但其在转录水平上对NF-κB依赖性基因的功能相关性及其生物学后果尚不清楚。我们研究了多柔比星诱导的乳腺癌细胞和不同遗传背景的新鲜人癌标本中NF-κB依赖性基因表达，重点是它们的p53状态。在用阿霉素和IKKβ抑制剂MLN 120 B处理的乳腺癌细胞中，通过基因表达微阵列鉴定了阿霉素的NF-κB依赖性特征，并在人癌症样本中离体证实。与p53的关联在功能上得到验证。最后，在一组接受基于阿霉素的辅助化疗的乳腺癌患者中测定NF-κB活化和p53状态。阿霉素处理p53突变的MDA-MB-231细胞导致NF NF-κB驱动的基因转录特征。在额外的阿霉素处理的细胞系和新鲜的原发性人乳腺肿瘤中证实了与侵袭、转移和化学抗性相关的基因（ICAM-1、CXCL 1、TNFAIP 3、IL 8）的调节。在这两个系统中，p53缺陷的背景与NF-κB依赖性信号的激活相关。此外，突变型p53 MDA-MB-231细胞中p53 WT的恢复损害了阿霉素诱导的NF-κB驱动的转录。此外，乳腺癌患者中p53缺陷背景和核NF-κB /p65与无病生存率降低相关。本研究支持p53缺陷是阿霉素驱动的NF-κB -反应所必需的，该反应限制了乳腺癌中阿霉素的细胞毒性，并与侵袭性临床行为相关。
NF-κB has been linked to doxorubicin resistance in breast cancer patients. NF-κB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-κB -dependent genes and the biological consequences are unclear. We studied NF-κB -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-κB -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-κB 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 NF-κB 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-defcient background correlated with the activation of the NF-κB -dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-κB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-κB /p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-κB -response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.
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影响因子：
3.7
作者：
Inglés-Esteve J;Morales M;Dalmases A;Garcia-Carbonell R;Jené-Sanz A;López-Bigas N;Iglesias M;Ruiz-Herguido C;Rovira A;Rojo F;Albanell J;Gomis RR;Bigas A;Espinosa L
通讯作者：
Espinosa L
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
4
作者：
Chen, Wenshu;Wang, Xia;Bai, Lang;Liang, Xiaomin;Zhuang, Jianguo;Lin, Yong
通讯作者：
Lin, Yong
影响因子：
3.1
作者：
Alsner, Jan;Jensen, Vibeke;Overgaard, Jens
通讯作者：
Overgaard, Jens
影响因子：
16
作者：
Campbell, KJ;Rocha, S;Perkins, ND
通讯作者：
Perkins, ND