E2F7 overexpression leads to tamoxifen resistance in breast cancer cells by competing with E2F1 at miR-15a/16 promoter.
E2F7 overexpression leads to tamoxifen resistance in breast cancer cells by competing with E2F1 at miR-15a/16 promoter.
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E2F7 过表达通过与 miR-15a/16 启动子上的 E2F1 竞争，导致乳腺癌细胞对他莫昔芬产生耐药性
DOI：
10.18632/oncotarget.5128
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Liu Q
中科院分区：
文献类型：
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作者：
Chu J;Zhu Y;Liu Y;Sun L;Lv X;Wu Y;Hu P;Su F;Gong C;Song E;Liu B;Liu Q
约50-70%的乳腺癌为雌激素受体α (ERα)阳性，其中大多数对包括他莫昔芬在内的内分泌治疗敏感。然而，这些患者中有三分之一最终会产生耐药性和复发。我们发现miR-15a和miR-16的表达在他莫昔芬耐药ER阳性乳腺癌细胞系中显著降低。外源性表达miR-15a/16通过抑制Cyclin E1和B细胞淋巴瘤-2 （Bcl-2）分别诱导细胞生长停滞和凋亡，模拟对他莫昔芬再敏化的耐药细胞。此外，我们发现E2F家族的一个抑制性成员E2F7通过与E2F1竞争宿主基因DLEU2启动子上的E2F结合位点来抑制miR-15a/16簇。此外，E2F7高表达与接受他莫昔芬治疗的乳腺癌患者复发风险高、预后差相关。总之，我们的研究结果表明，过表达E2F7抑制miR-15a/16，然后增加Cyclin E1和Bcl-2，导致他莫昔芬耐药。E2F7可能是乳腺癌他莫昔芬耐药的一个有价值的预后标志物和治疗靶点。
About 50–70% of breast cancers are estrogen receptor α (ERα) positive and most of them are sensitive to endocrine therapy including tamoxifen. However, one third of these patients will eventually develop resistance and relapse. We found that the expression of miR-15a and miR-16 were significantly decreased in tamoxifen resistant ER positive breast cancer cell lines. Exogenous expression of miR-15a/16 mimics re-sensitized resistant cells to tamoxifen by inhibiting Cyclin E1 and B cell lymphoma-2 (Bcl-2) to induce cell growth arrest and apoptosis respectively. Further, we identified that a repressive member of E2F family, E2F7, was responsible for the suppression of miR-15a/16 cluster by competing with E2F1 for E2F binding site at the promoter of their host gene DLEU2. Moreover, high expression of E2F7 is correlated with high risk of relapse and poor prognosis in breast cancer patients receiving tamoxifen treatment. Together, our results suggest that overexpression of E2F7 represses miR-15a/16 and then increases Cyclin E1 and Bcl-2 that result in tamoxifen resistance. E2F7 may be a valuable prognostic marker and a therapeutic target of tamoxifen resistance in breast cancer.