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首页> 外文期刊>Neoplasia: an international journal for oncology research >Deptor Enhances Triple-Negative Breast Cancer Metastasis and Chemoresistance through Coupling to Survivin Expression
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Deptor Enhances Triple-Negative Breast Cancer Metastasis and Chemoresistance through Coupling to Survivin Expression

机译：去普罗斯通过偶联至存活者的表达增强三阴性乳腺癌转移和化学抑制性

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Transforming growth factor–β (TGF-β) functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs). Precisely how TGF-β acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR) inhibitor, Dep domain–containing mTOR-interacting protein (Deptor), in coupling TGF-β to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1) inversely correlated with the metastatic ability of human (MCF10A) and mouse (4T1) TNBC progression series and 2) robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor α–negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1) organoid growth in vitro, 2) pulmonary outgrowth in mice, and 3) resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli.
机译：转化生长因子-β（TGF-β）抑制正常乳腺组织和早期乳腺癌中的肿瘤内酯，并矛盾，促进后期乳腺癌，特别是三阴性乳腺癌的转移和化学性（TNBCS ）。恰恰如何在晚期乳腺癌中获取致癌特性仍然未知，同时雷帕霉素（MTOR）抑制剂，含Dep结构域的MTOR-相互作用蛋白（Deptor）的作用，偶联TGF-β的作用TNBC开发和转移性进展。在这里，我们证明了除了它们的腔体对应物中的基础/ TNBC中的表达式表达。另外，去普体表达是1）与人（MCF10A）和小鼠（4T1）TNBC进展系列和2）的转移能力与由上皮 - 间充质转换程序的几种诱导者鲁棒地抑制。在4T07细胞中的去普体表达的功能破坏显着抑制它们在体外的增殖和有机体生长，以及预防小鼠肺部的殖民化和肿瘤形成。在缺口对比中，升高的去普体表达与患有雌激素受体α阴性乳腺癌的患者的较差的整体存活率显着相关。因此，MDA-MB-231细胞中的强制除去剂表达在小鼠中大大增强了它们的1）个体体外生长，以及3）对化学疗法的抗性，依赖于去普通对Survivin表达的事件。集体，我们的研究结果突出了去普体在转移期间调节TNBCS的增殖和存活的二分函数;它们还致力于去普体及其对Survivin的刺激，作为TNBC抗化学疗法和凋亡刺激的基本组分。

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