High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.
High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.
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DOI：
10.1158/0008-5472.can-10-1590
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Garabedian MJ
中科院分区：
文献类型：
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作者：
Simpson NE;Lambert WM;Watkins R;Giashuddin S;Huang SJ;Oxelmark E;Arju R;Hochman T;Goldberg JD;Schneider RJ;Reiz LF;Soares FA;Logan SK;Garabedian MJ
p23是位于细胞质和细胞核中的Hsp 90共伴侣蛋白，其稳定未配体的类固醇受体，控制某些激酶的催化活性，调节蛋白质-DNA动力学，并且在几种癌症中上调。我们以前证明，p23过表达的MCF-7细胞（MCF-7+p23）表现出增加的侵袭性，而不影响雌激素依赖的增殖反应，这表明，p23差异调节基因控制过程与乳腺肿瘤转移。为了全面了解p23对雌激素受体（ER）依赖性和非依赖性基因表达的影响，我们分析了对照组与MCF-7+p23细胞在雌激素存在和不存在下的mRNA表达。一些p23敏感的靶基因参与转移和耐药被确定。最引人注目的是，这些基因中的许多基因在浸润性乳腺癌中也存在失调，包括PMP 22、ABCC 3、AGR 2、Sox 3、TM 4SF 1和p8（NUPR 1）。通过p23上调ATP依赖性转运蛋白ABCC 3可使MCF-7+p23细胞对化疗药物依托泊苷和阿霉素产生耐药性。MCF-7+p23细胞也显示出相对于对照细胞更高水平的活化Akt和扩增的磷酸化蛋白质组，表明升高的p23也增强了细胞质信号传导途径。对于乳腺癌患者，肿瘤分期和细胞质p23高表达比单独分期更准确地预测疾病复发和死亡率。高核p23被发现与高细胞质p23相关，因此两者都可能通过增加乳腺癌患者的转移潜力和耐药性而促进肿瘤进展和不良预后。
p23 is an Hsp90 co-chaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls catalytic activity of certain kinases, regulates protein-DNA dynamics and is upregulated in several cancers. We previously demonstrated that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients.