Breast Cancer Resistance to Antiestrogens Is Enhanced by Increased ER Degradation and ERBB2 Expression
Breast Cancer Resistance to Antiestrogens Is Enhanced by Increased ER Degradation and ERBB2 Expression
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DOI：
10.1158/0008-5472.can-16-1593
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Ono, Mayumi
中科院分区：
文献类型：
--
作者：
Shibata, Tomohiro;Watari, Kosuke;Ono, Mayumi
内分泌治疗有效地改善了雌激素受体(ER)阳性乳腺癌患者的预后。然而，耐药肿瘤的出现带来了一个核心的临床挑战。在对抗雌激素福尔维斯特耐药的乳腺癌细胞中，我们确定了转录因子YBX1以及ER和ERBB2受体水平的致病机制作用。YBX1在亲本细胞中的强制表达在体内外对他莫昔芬和弗维斯特具有耐药性。此外，YBX1的过表达分别与ER和ERBB2的表达水平降低和升高有关。在抗雌激素耐药细胞中，YBX1磷酸化增加与ER降解率增加4倍相关。值得注意的是，YBX1与ER结合，导致其蛋白酶体加速降解，并诱导ERBB2的转录激活。同时，三苯氧胺处理也增强了YBX1与ERBB2启动子的结合，从而诱导ERBB2表达增加。总之，这些发现确定了YBX1在乳腺癌细胞中参与抗雌激素旁路的耐药机制。(C)2016年AACR。
Endocrine therapies effectively improve the outcomes of patients with estrogen receptor (ER)-positive breast cancer. However, the emergence of drug-resistant tumors creates a core clinical challenge. In breast cancer cells rendered resistant to the antiestrogen fulvestrant, we defined causative mechanistic roles for the transcription factor YBX1 and the levels of ER and the ERBB2 receptor. Enforced expression of YBX1 in parental cells conferred resistance against tamoxifen and fulvestrant in vitro and in vivo. Furthermore, YBX1 overexpression was associated with decreased and increased levels of ER and ERBB2 expression, respectively. In antiestrogen-resistant cells, increased YBX1 phosphorylation was associated with a 4-fold higher degradation rate of ER. Notably, YBX1 bound the ER, leading to its accelerated proteasomal degradation, and induced the transcriptional activation of ERBB2. In parallel fashion, tamoxifen treatment also augmented YBX1 binding to the ERBB2 promoter to induce increased ERBB2 expression. Together, these findings define a mechanism of drug resistance through which YBX1 contributes to antiestrogen bypass in breast cancer cells. (C) 2016 AACR.