MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway.
MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway.
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DOI：
10.1186/1471-2407-14-869
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发表时间：
2014-11-24
期刊：
影响因子：
3.8
通讯作者：
Xie X
中科院分区：
文献类型：
--
作者：
Du C;Yi X;Liu W;Han T;Liu Z;Ding Z;Zheng Z;Piao Y;Yuan J;Han Y;Xie M;Xie X
曲妥珠单抗耐药在人类表皮生长因子受体(HER)2阳性乳腺癌的治疗中几乎是不可避免的，这与10号染色体缺失的磷酸酶和张力蛋白同源基因(PTEN)丢失有关。由于甲粘附素促进乳腺癌的恶性表型，我们试图确定甲粘附素是否通过降低抑癌基因κB依赖的途径促进曲妥珠单抗的耐药。分析HER2阳性乳腺癌组织和曲妥珠单抗耐药SK-BR-3(SK-BR-3/R)细胞中MTDH和PTEN表达的相关性。通过基因敲除或过表达来调控MTDH和PTEN水平，以阐明MTDH和PTEN在曲妥珠单抗耐药中的分子机制。在体内研究中，将SK-BR-3和SK-BR-3/R细胞及其修饰的衍生物单独或在曲妥珠单抗暴露下接种到裸鼠体内。肿瘤体积、组织学检查以及Ki67和PTEN的表达。在HER2阳性乳腺癌患者和SK-BR-3/R细胞中，MTDH表达升高提示临床疗效差，无进展生存时间缩短，并与PTEN水平呈负相关。MTDH基因敲除恢复了SK-BR-3/R细胞中PTEN的表达和对曲妥珠单抗的敏感性，而MTDH的过表达可能通过抑制IκBα和p65的核转位从而降低了PTEN的表达，从而阻止了曲妥珠单抗作用下SK-BR-3细胞的死亡。MTDH和p65共转染后，PTEN的协同作用被观察到。在SK-BR-3/R细胞中强制表达PTEN可恢复曲妥珠单抗的敏感性。此外，转基因乳腺癌SK-BR-3/R细胞皮下移植瘤的肿瘤体积和Ki67水平降低，PTEN表达增加，而高表达的SK-BR-3细胞的移植瘤则相反。在HER2阳性乳腺癌中，mtdh过表达使曲妥珠单抗耐药。亚甲基四氢叶酸脱氢酶通过依赖于核因子κB的途径抑制抑癌基因PTEN，至少部分地通过抑制曲妥珠单抗耐药，有望成为治疗HER2阳性乳腺癌的靶点。本文的在线版本(DOI：10.1186/1471-2407-14-869)包含补充材料，可供授权用户使用。
Trastuzumab resistance is almost inevitable in the management of human epidermal growth factor receptor (HER) 2 positive breast cancer, in which phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss is implicated. Since metadherin (MTDH) promotes malignant phenotype of breast cancer, we sought to define whether MTDH promotes trastuzumab resistance by decreasing PTEN expression through an NFκB-dependent pathway. The correlations between MTDH and PTEN expressions were analyzed both in HER2 positive breast cancer tissues and trastuzumab resistant SK-BR-3 (SK-BR-3/R) cells. Gene manipulations of MTDH and PTEN levels by knockdown or overexpression were utilized to elucidate molecular mechanisms of MTDH and PTEN implication in trastuzumab resistance. For in vivo studies, SK-BR-3 and SK-BR-3/R cells and modified derivatives were inoculated into nude mice alone or under trastuzumab exposure. Tumor volumes, histological examinations as well as Ki67 and PTEN expressions were revealed. Elevated MTDH expression indicated poor clinical benefit, shortened progression free survival time, and was negatively correlated with PTEN level both in HER2 positive breast cancer patients and SK-BR-3/R cells. MTDH knockdown restored PTEN expression and trastuzumab sensitivity in SK-BR-3/R cells, while MTDH overexpression prevented SK-BR-3 cell death under trastuzumab exposure, probably through IκBα inhibition and nuclear translocation of p65 which subsequently decreased PTEN expression. Synergized effect of PTEN regulation were observed upon MTDH and p65 co-transfection. Forced PTEN expression in SK-BR-3/R cells restored trastuzumab sensitivity. Furthermore, decreased tumor volume and Ki67 level as well as increased PTEN expression were observed after MTDH knockdown in subcutaneous breast cancer xenografts from SK-BR-3/R cells, while the opposite effect were found in grafts from MTDH overexpressing SK-BR-3 cells. MTDH overexpression confers trastuzumab resistance in HER2 positive breast cancer. MTDH mediates trastuzumab resistance, at least in part, by PTEN inhibition through an NFκB-dependent pathway, which may be utilized as a promising therapeutic target for HER2 positive breast cancer. The online version of this article (doi:10.1186/1471-2407-14-869) contains supplementary material, which is available to authorized users.
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作者：
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