Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression.
Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression.
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DOI：
10.1016/j.neo.2015.02.003
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发表时间：
2015-03
期刊：
影响因子：
4.8
通讯作者：
Schiemann, William P.
中科院分区：
文献类型：
--
作者：
Parvani, Jenny G.;Davuluri, Gangarao;Wendt, Michael K.;Espinosa, Christine;Tian, Maozhen;Danielpour, David;Sossey-Alaoui, Khalid;Schiemann, William P.
转化生长因子-β (TGF-β) 的作用是抑制正常乳腺组织和早期乳腺癌的肿瘤发生，但矛盾的是，它还能促进晚期乳腺癌，特别是三阴性乳腺癌 (TNBC) 的转移和化疗耐药性。 TGF-β 到底如何在晚期乳腺癌中获得致癌特征仍不清楚，内源性哺乳动物雷帕霉素靶点 (mTOR) 抑制剂、包含 Dep 结构域的 mTOR 相互作用蛋白 (Deptor) 在 TGF-β 与 TNBC 发展和转移进展的耦合中的作用仍然未知。在这里，我们证明 Deptor 表达在 basal-like/TNBC 中相对于它们的腔内对应物下调。此外，Deptor 表达 1) 与人类 (MCF10A) 和小鼠 (4T1) TNBC 进展系列的转移能力呈负相关，2) 受到上皮-间质转化程序的几种诱导剂的强烈抑制。 4T07 细胞中 Deptor 表达的功能性破坏显着抑制了它们的体外增殖和类器官生长，并阻止了它们在小鼠肺部的定植和肿瘤形成。与此形成鲜明对比的是，Deptor 表达升高与雌激素受体 α 阴性乳腺癌患者的总体生存率较差显着相关。因此，在 MDA-MB-231 细胞中强制表达 Deptor 可以显着增强其 1) 体外类器官生长，2) 小鼠肺部生长，以及 3) 对化疗的抵抗力，这一事件依赖于 Deptor 与存活蛋白表达的偶联。总的来说，我们的研究结果强调了 Deptor 在调节转移过程中 TNBC 的增殖和存活方面的二分功能；他们还指出 Deptor 及其对生存素的刺激是 TNBC 对化疗和细胞凋亡刺激产生耐药性的重要组成部分。
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.
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影响因子：
3.7
作者：
Kadota M;Yang HH;Gomez B;Sato M;Clifford RJ;Meerzaman D;Dunn BK;Wakefield LM;Lee MP
通讯作者：
Lee MP
影响因子：
3.6
作者：
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Tamaki, K
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4.3
作者：
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Schulze A
影响因子：
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作者：
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通讯作者：
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影响因子：
7.3
作者：
Gellibert, FO;Woolven, J;Hartley, D
通讯作者：
Hartley, D