Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer.
Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer.
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DOI：
10.1038/s41467-018-07264-0
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发表时间：
2018-11-09
影响因子：
16.6
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Liu Y;Xu J;Choi HH;Han C;Fang Y;Li Y;Van der Jeught K;Xu H;Zhang L;Frieden M;Wang L;Eyvani H;Sun Y;Zhao G;Zhang Y;Liu S;Wan J;Huang C;Ji G;Lu X;He X;Zhang X
染色体17q23扩增发生在约11%的人类乳腺癌中。在乳腺癌中，17q23扩增富含HER2+，与不良的临床结果显著相关。除了先前发现的癌基因Wip1外，我们在大多数包含Wip1的17q23扩增片段中发现了一个致癌microRNA基因MIR21。17q23扩增导致Wip1和miR-21的异常表达，这不仅促进了乳腺肿瘤的发生，而且导致了对抗HER2治疗的抵抗。抑制Wip1和miR-21选择性地抑制携带17q23扩增的HER2+乳腺癌细胞的增殖、存活和致瘤潜力。为了克服体内曲妥珠单抗治疗的耐药性，我们开发了pH敏感的纳米颗粒，用于将Wip1和miR-21抑制剂特异性地共输送到HER2+乳腺肿瘤中，导致肿瘤生长显著减少。这些结果证明了Wip1和miR-21抑制剂联合治疗曲妥珠单抗耐药的HER2+乳腺癌的巨大潜力。含有Wip1癌基因的17q23扩增子在HER2+乳腺癌中经常被扩增。在这里，他们发现MIR21存在于含有Wip1的扩增片段中，并报告了基于纳米颗粒的Wip1和miR-21抑制剂的联合传递对曲妥珠单抗耐药HER2+乳腺癌有效。
Chromosome 17q23 amplification occurs in ~11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers. The 17q23 amplicon containing the WIP1 oncogene is frequently amplified in HER2+ breast cancer. Here they find MIR21 to be present in WIP1-containing amplicons, and report nanoparticle based co-delivery of WIP1 and miR-21 inhibitors to be effective in trastuzumab-resistant HER2+ breast cancer.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
癌症中的microRNA生物发生途径。
DOI：
10.1038/nrc3932
发表时间：
2015-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Lin S;Gregory RI
通讯作者：
Gregory RI
影响因子：
64.8
作者：
Chendrimada, TP;Gregory, RI;Shiekhattar, R
通讯作者：
Shiekhattar, R
影响因子：
64.8
作者：
Liu, Yunhua;Zhang, Xinna;Lu, Xiongbin
通讯作者：
Lu, Xiongbin
影响因子：
64.5
作者：
Ciriello G;Gatza ML;Beck AH;Wilkerson MD;Rhie SK;Pastore A;Zhang H;McLellan M;Yau C;Kandoth C;Bowlby R;Shen H;Hayat S;Fieldhouse R;Lester SC;Tse GM;Factor RE;Collins LC;Allison KH;Chen YY;Jensen K;Johnson NB;Oesterreich S;Mills GB;Cherniack AD;Robertson G;Benz C;Sander C;Laird PW;Hoadley KA;King TA;TCGA Research Network;Perou CM
通讯作者：
Perou CM