Alteration of Y-box binding protein-1 expression modifies the response to endocrine therapy in estrogen receptor-positive breast cancer
Alteration of Y-box binding protein-1 expression modifies the response to endocrine therapy in estrogen receptor-positive breast cancer
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DOI：
10.1007/s10549-011-1731-8
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Ito, Ken-ichi
中科院分区：
文献类型：
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作者：
Ito, Tokiko;Kamijo, Shinobu;Ito, Ken-ichi
Y-box结合蛋白-1（YB-1）在肿瘤的进展和耐药中起重要作用。本研究检测了YB-1是否参与雌激素受体（ER）阳性乳腺癌细胞对内分泌治疗反应的改变。建立稳定表达YB-1的MCF 7细胞（MCF 7-YB-1）和载体对照细胞（MCF 7-vector）。这些细胞用于分析ER和生长因子受体信号通路相关因子的表达以及对抗雌激素（他莫昔芬和氟维司群）和雌激素反应元件（ERE）活性的反应。在野生型MCF 7细胞中测试敲低内源性YB-1表达的效果。此外，我们还检测了YB-1的表达以及ER和生长因子受体信号通路相关因子在术前化疗的临床乳腺癌中的表达。MCF 7-YB-1细胞中HER 2、AIB 1、p-Erk和c-Myc的表达增加。相反，敲低YB-1降低了这些因子的表达，但增加了野生型MCF 7细胞中ER α的表达。此外，与MCF 7载体细胞相比，MCF 7-YB-1对抗雌激素的敏感性降低。将YB-1导入MCF 7细胞中，可抑制抗雌激素诱导的MCF 7细胞凋亡和细胞周期阻滞于G1期。在MCF 7-YB-1细胞中，当细胞用他莫昔芬或氟维司群处理时，p-Erk和c-Myc的表达水平持续上调。与MCF 7-载体细胞相比，MCF 7-YB-1细胞中的ERE活性降低，并且在低于抑制MCF 7-载体细胞中的ERE活性的浓度下，氟维司群抑制MCF 7-YB-1细胞中的ERE活性。在术前化疗治疗的ER阳性临床乳腺癌中，化疗后YB-1表达增加或阳性的标本中HER 2表达阳性的标本数量显著增加。这些数据表明，YB-1的改变可能会改变ER阳性乳腺癌细胞中ER途径和HER 2途径之间的串扰，因此，可能会改变ER阳性乳腺癌细胞对内分泌治疗的反应。
Y-box binding protein-1 (YB-1) plays an important role in tumor progression and drug resistance. This study examined whether YB-1 is involved in the alteration of response to endocrine therapy in estrogen receptor (ER)-positive breast cancer cells. MCF7 cells that stably expressed YB-1 (MCF7-YB-1) and vector control cells (MCF7-vector) were established. These cells were used to analyze the expression of the factors related to ER and growth factor receptor signaling pathways and responses to antiestrogens (tamoxifen and fulvestrant) and estrogen responsive element (ERE) activity. The effect of knocking down endogenous YB-1 expression was tested in wild-type MCF7 cells. In addition, the expression of YB-1 and the factors related to ER and growth factor receptor signaling pathways were evaluated in clinical breast cancers treated with preoperative chemotherapy. The expression of HER2, AIB1, p-Erk, and c-Myc was increased in MCF7-YB-1 cells. In contrast, knocking down of YB-1 decreased the expression of these factors but increased the expression of ER alpha in wild-type MCF7 cells. Furthermore, sensitivity to antiestrogens was decreased in the MCF7-YB-1 in comparison to that in MCF7-vector cells. The introduction of YB-1 into MCF7 cells inhibited apoptosis and cell cycle arrest at G1 phase induced by antiestrogens. In MCF7-YB-1 cells, the expression levels of p-Erk and c-Myc were continuously upregulated when cells were treated with either tamoxifen or fulvestrant. The ERE activity was reduced in MCF7-YB-1 cells in comparison to MCF7-vector cells, and the ERE activity in MCF7-YB-1 cells was inhibited by fulvestrant at a lower concentration than that which inhibited the ERE activity in MCF7-vector cells. In ER-positive clinical breast cancers treated with preoperative chemotherapy, significantly more number of specimens that showed increased or positive YB-1 expression after chemotherapy was positive for HER2 expression. These data suggest that alteration of YB-1 may modify the crosstalk between the ER pathway and HER2 pathway in ER-positive breast cancer cells, and consequently, may alter the response to endocrine therapy in ER-positive breast cancer cells.