Targeting thyroid hormone receptor beta in triple-negative breast cancer.
Targeting thyroid hormone receptor beta in triple-negative breast cancer.
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DOI：
10.1007/s10549-015-3354-y
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发表时间：
2015-04
影响因子：
3.8
通讯作者：
Fuqua, Suzanne A. W.
中科院分区：
文献类型：
--
作者：
Gu, Guowei;Gelsomino, Luca;Covington, Kyle R.;Beyer, Amanda R.;Wang, John;Rechoum, Yassine;Huffman, Kenneth;Carstens, Ryan;Ando, Sebastiano;Fuqua, Suzanne A. W.
关键词：
在三阴性乳腺癌中发现新的核受体靶点表达微阵列、蛋白质印迹、qRT-PCR、MTT生长测定、软琼脂锚定非依赖性生长测定、TRE报告基因反式激活测定、统计分析。我们对227例三阴性乳腺肿瘤进行了微阵列分析，并根据其核受体表达将肿瘤分为五组。甲状腺激素受体β（TRβ）是第5组与其他组相比表达差异最大的核受体之一。TRβ低表达的患者与不良结局相关。我们评估了TRβ在代表第5组肿瘤的三阴性乳腺癌细胞系中的作用。TRβ的敲除增加了软琼脂集落，并降低了对多西他赛和多柔比星治疗的敏感性。多西他赛或阿霉素长期培养的细胞系也表达减少的TRβ蛋白。芯片分析显示cAMP/PKA信号是TRβ敲低细胞中唯一上调的KEGG通路。cAMP或PKA的抑制剂与阿霉素组合进一步增强细胞凋亡并恢复对化疗的敏感性。TRβ特异性激动剂增强TRβ表达，并进一步使细胞对多西他赛和多柔比星敏感。致敏作用由细胞凋亡增加和裂解PARP和caspase 3升高介导。TRβ代表三阴性乳腺癌的一种新型核受体靶点;低TRβ水平与多西他赛和多柔比星治疗的耐药性增强相关。TRβ特异性激动剂增强对这两种药物的化学敏感性。机械增强的cAMP/PKA信号传导与TRβ对化疗反应的影响相关。
Discover novel nuclear receptor targets in triple negative breast cancer Expression microarray, western blot, qRT-PCR, MTT growth assay, soft agar anchorage-independent growth assay, TRE reporter transactivation assay, statistical analysis. We performed microarray analysis using 227 triple negative breast tumors, and clustered the tumors into five groups according to their nuclear receptor expression. Thyroid hormone receptor beta (TRβ) was one of the most differentially expressed nuclear receptors in group 5 compared to other groups. TRβ low expressing patients were associated with poor outcome. We evaluated the role of TRβ in triple negative breast cancer cell lines representing group 5 tumors. Knockdown of TRβ increased soft agar colony and reduced sensitivity to docetaxel and doxorubicin treatment. Docetaxel or doxorubicin long-term cultured cell lines also expressed decreased TRβ protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TRβ knockdown cells. Inhibitors of cAMP or PKA, in combination with doxorubicin further enhanced cell apoptosis and restored sensitivity to chemotherapy. TRβ-specific agonists enhanced TRβ expression, and further sensitized cells to both docetaxel and doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and caspase 3. TRβ represents a novel nuclear receptor target in triple negative breast cancer; low TRβ levels were associated with enhanced resistance to both docetaxel and doxorubicin treatment. TRβ-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TRβ’s effects on response to chemotherapy.
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乳腺癌患者化疗期间甲状腺功能下降的意义：三碘甲状腺原氨酸的化疗增敏作用。
影响因子：
3.8
作者：
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Hortobagyi, GN
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通讯作者：
Baselga, Jose
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