Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer
Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer
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SALL2的表观遗传沉默导致乳腺癌对他莫昔芬产生耐药性
DOI：
10.15252/emmm.201910638
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发表时间：
2019-10-28
影响因子：
11.1
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Ye, Liping;Lin, Chuyong;Song, Libing
对他莫昔芬的耐药性是乳腺癌治疗的临床主要挑战。尽管雌激素受体-α(ERα)下调是他莫昔芬耐药的主要机制，但在他莫昔芬治疗期间ERα下降的原因仍然不清楚。在此，我们通过对9对初发的三苯氧胺治疗前的乳腺癌组织和复发的三苯氧胺耐药乳腺癌组织的转录谱分析，发现在他莫昔芬治疗期间，Spalt样转录因子2(SALL2)的表达显著降低。SALL2通过直接与DNA启动子结合，上调ESR1和PTEN的转录水平。相比之下，沉默SALL2诱导ERα和PTEN下调并激活Akt/mTOR信号，导致ERα阳性乳腺癌的雌激素非依赖性生长和他莫昔芬耐药。此外，在对他莫昔芬耐药的乳腺癌中发现了SALL2启动子的高甲基化。重要的是，体内实验表明，DNA甲基转移酶抑制剂介导的SALL2修复使三苯氧胺耐药乳腺癌对他莫昔芬治疗再次增敏。这些发现阐明了SALL2调节ER的机制，并代表了一个潜在的临床特征，可用于对可能受益于他莫昔芬和DNMT抑制剂联合治疗的乳腺癌患者进行分类。
Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor-alpha (ER alpha) is the dominant mechanism of tamoxifen resistance, the reason for ER alpha decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt-like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre-tamoxifen-treated and relapsed tamoxifen-resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ER alpha and PTEN and activated the Akt/mTOR signaling, resulting in estrogen-independent growth and tamoxifen resistance in ER alpha-positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen-resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor-mediated SALL2 restoration resensitized tamoxifen-resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co-therapy with tamoxifen and DNMT inhibitor.