MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer.
MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer.
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DOI：
10.1016/j.ccr.2008.11.013
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发表时间：
2009-01-06
期刊：
影响因子：
50.3
通讯作者：
Kang Y
中科院分区：
文献类型：
--
作者：
Hu G;Chong RA;Yang Q;Wei Y;Blanco MA;Li F;Reiss M;Au JL;Haffty BG;Kang Y
转移性疾病的靶向治疗依赖于从大量随机遗传改变中鉴定功能重要的转移基因。在这里，我们使用计算算法来映射与预后不良乳腺癌相关的最小复发性基因组改变。通过这种方法鉴定了8q22基因组增益，并在广泛收集的乳腺肿瘤样品中进行了验证。8q22的区域获得提高了转移基因Metadherin（MTDH）的表达，MTDH在超过40%的乳腺癌中过表达，并与不良临床结局相关。MTDH的功能特征揭示了其在促进转移性播种和增强化疗抗性中的双重作用。这些发现确立了MTDH作为同时增强化疗疗效和降低转移风险的重要治疗靶点。乳腺癌的基因组分析已经建立了几个临床适用的预后不良的基因签名。然而，独立标签之间缺乏重叠阻止了标签中功能重要基因的鉴定。在这里，我们报告了一个综合性的策略，以确定复发性基因组改变，这是临床相关的和功能上重要的乳腺癌进展。这种方法的成功应用导致在复发性8q22不良预后基因组获得中鉴定MTDH，其在转移和化疗抗性中具有重要功能。MTDH的双重功能进一步为关于原发性肿瘤中转移基因的选择的长期存在的概念困境提供了解释。总的来说，我们的数据说明了生物信息学与临床和实验转移研究相结合的协同价值。
Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates the expression of metastasis gene Metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk. Genomic profiling of breast cancer has established several clinically applicable poor-prognosis gene signatures. However, the lack of overlap between independent signatures prevents the identification of functionally important genes in the signatures. Here we report an integrative strategy to identify recurrent genomic alterations that are both clinically relevant and functionally important for breast cancer progression. Successful application of this approach lead to the identification of MTDH at the recurrent 8q22 poor-prognosis genomic gain with important functions in both metastasis and chemoresistance. The dual-functionality of MTDH further provides an explanation for the long standing conceptual dilemma regarding the selection of metastasis genes in the primary tumor. Overall, our data illustrate the synergistic value of integrating bioinformatics with clinical and experimental metastasis research.
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