Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation.
Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation.
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DOI：
10.7150/ijbs.11380
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发表时间：
2015
影响因子：
9.2
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Ma G;He J;Yu Y;Xu Y;Yu X;Martinez J;Lonard DM;Xu J
Twist1是驱动乳腺癌细胞上皮间质转化、侵袭和转移的转录因子。种系Twist1敲除的小鼠胚胎致死，而诱导型Twist1敲除的成年小鼠没有明显的健康问题，这表明Twist1是抑制成年患者乳腺癌侵袭和转移的可行治疗靶点。在这项研究中，我们在 HeLa 细胞中表达荧光素酶蛋白或 Twist1-荧光素酶融合蛋白，作为高通量系统的一部分，以筛选 Sigma-Aldrich 药理活性化合物库 (LOPAC) 中的 1280 种化合物，了解它们对 Twist1 蛋白表达的影响。最有趣的化合物之一是他莫昔芬，一种选择性雌激素受体 (ER) 调节剂，用于治疗 ER 阳性乳腺癌。他莫昔芬治疗显着加速了多种细胞系中 Twist1 的降解，包括 HEK293 人肾细胞、异位或内源表达 Twist1 的 4T1 和 168FARN 小鼠乳腺肿瘤细胞。他莫昔芬诱导的 Twist1 降解可以被 MG132 蛋白酶体抑制剂阻断，表明他莫昔芬通过泛素化蛋白酶体途径诱导 Twist1 降解。然而，他莫昔芬诱导的 Twist1 降解与这些细胞中 Twist1 mRNA 表达、雌激素信号传导和 MAPK 介导的 Twist1 磷酸化无关。重要的是，他莫昔芬还显着抑制了 SCID-bg 小鼠 ER 阴性 4T1 乳腺肿瘤细胞的基质胶侵袭行为和肺转移，这些肿瘤细胞依赖于内源性 Twist1 进行侵袭和转移。这些结果表明，他莫昔芬可以显着加速Twist1降解，从而抑制癌细胞的侵袭和转移，这表明他莫昔芬不仅可以用于治疗ER阳性乳腺癌，还可以减少Twist1介导的ER阴性乳腺癌的侵袭和转移。
Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers.
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影响因子：
8.8
作者：
Ferlini, C;Scambia, G;Marone, M;Distefano, M;Gaggini, C;Ferrandina, G;Fattorossi, A;Isola, G;Benedetti Panici, P;Mancuso, S
通讯作者：
Mancuso, S
影响因子：
4.6
作者：
Coskun, U;Gunel, N;Cihan, A
通讯作者：
Cihan, A
影响因子：
44.1
作者：
Fu, Junjiang;Qin, Li;Xu, Jianming
通讯作者：
Xu, Jianming
影响因子：
4.4
作者：
Nalbandian, G;Paharkova-Vatchkova, V;Kovats, S
通讯作者：
Kovats, S
TWIST 通过在乳腺癌细胞中募集 NuRD 蛋白复合物来抑制雌激素受体 α 的表达。
影响因子：
9.2
作者：
Fu J;Zhang L;He T;Xiao X;Liu X;Wang L;Yang L;Yang M;Zhang T;Chen R;Xu J
通讯作者：
Xu J