Combined histone deacetylase inhibition and tamoxifen induces apoptosis in tamoxifen-resistant breast cancer models, by reversing Bcl-2 overexpression.
Combined histone deacetylase inhibition and tamoxifen induces apoptosis in tamoxifen-resistant breast cancer models, by reversing Bcl-2 overexpression.
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DOI：
10.1186/s13058-015-0533-z
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发表时间：
2015-02-25
期刊：
影响因子：
--
通讯作者：
Munster PN
中科院分区：
文献类型：
--
作者：
Raha P;Thomas S;Thurn KT;Park J;Munster PN
尽管雌激素受体（ER）持续表达，但激素治疗抵抗的出现是治疗乳腺癌的主要挑战。最近的临床研究表明，组蛋白脱乙酰酶（HDAC）抑制剂逆转激素治疗抵抗的表观遗传调节。然而，很少有人知道后天激素抵抗过程中的ER的表观遗传调制。我们最近的II期研究表明，HDAC抑制剂使激素治疗抵抗性肿瘤对抗雌激素他莫昔芬重新敏感。在这项研究中，我们试图了解这种组合的功效背后的机制。我们通过将ER阳性MCF 7和T47 D细胞分别连续暴露于4-羟基他莫昔芬超过12个月，产生了对他莫昔芬耐药的细胞系，命名为TAMRM和TAMRT。HDAC抑制，沿着药理学和遗传学操作的关键生存途径，包括ER和Bcl-2，被用来表征这些耐药模型。TAMRM细胞显示对他莫昔芬、氟维司群和雌激素剥夺的敏感性降低。与先前的模型一致，ER表达被保留，并且该基因没有突变。与亲本MCF 7细胞相比，TAMRM中ER表达升高，而孕酮受体（PGR）丢失。ER对配体的敏感性大大降低，经典的ER反应基因被抑制。该模型通过Bcl-2和c-Myc的转录上调以及细胞周期检查点蛋白p21的下调来传递他莫昔芬抗性，表现为加速生长和减少细胞死亡。与TAMRM细胞类似，TAMRT细胞系表现出显著降低的他莫昔芬敏感性、增加的ER和Bcl-2表达以及显著降低的PGR表达。用HDAC抑制剂治疗逆转了改变的转录事件，并重新建立了ER对他莫昔芬的敏感性，导致Bcl-2的显著下调、生长停滞和细胞凋亡。Bcl-2的选择性抑制反映了HDAC抑制剂存在下的这些效果。我们的模型暗示升高的ER和Bcl-2是抗雌激素抵抗的关键驱动因素，这可以通过HDAC抑制通过表观遗传调节来逆转。本文的在线版本（doi：10.1186/s13058-015-0533-z）包含补充材料，可供授权用户使用。
The emergence of hormone therapy resistance, despite continued expression of the estrogen receptor (ER), is a major challenge to curing breast cancer. Recent clinical studies suggest that epigenetic modulation by histone deacetylase (HDAC) inhibitors reverses hormone therapy resistance. However, little is known about epigenetic modulation of the ER during acquired hormone resistance. Our recent phase II study demonstrated that HDAC inhibitors re-sensitize hormone therapy-resistant tumors to the anti-estrogen tamoxifen. In this study, we sought to understand the mechanism behind the efficacy of this combination. We generated cell lines resistant to tamoxifen, named TAMRM and TAMRT, by continuous exposure of ER-positive MCF7 and T47D cells, respectively to 4-hydroxy tamoxifen for over 12 months. HDAC inhibition, along with pharmacological and genetic manipulation of key survival pathways, including ER and Bcl-2, were used to characterize these resistant models. The TAMRM cells displayed decreased sensitivity to tamoxifen, fulvestrant and estrogen deprivation. Consistent with previous models, ER expression was retained and the gene harbored no mutations. Compared to parental MCF7 cells, ER expression in TAMRM was elevated, while progesterone receptor (PGR) was lost. Sensitivity of ER to ligands was greatly reduced and classic ER response genes were suppressed. This model conveyed tamoxifen resistance through transcriptional upregulation of Bcl-2 and c-Myc, and downregulation of the cell cycle checkpoint protein p21, manifesting in accelerated growth and reduced cell death. Similar to TAMRM cells, the TAMRT cell line exhibited substantially decreased tamoxifen sensitivity, increased ER and Bcl-2 expression and significantly reduced PGR expression. Treatment with HDAC inhibitors reversed the altered transcriptional events and reestablished the sensitivity of the ER to tamoxifen resulting in substantial Bcl-2 downregulation, growth arrest and apoptosis. Selective inhibition of Bcl-2 mirrored these effects in presence of an HDAC inhibitor. Our model implicates elevated ER and Bcl-2 as key drivers of anti-estrogen resistance, which can be reversed by epigenetic modulation through HDAC inhibition. The online version of this article (doi:10.1186/s13058-015-0533-z) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
Hellemans, P;van Dam, P A;Weyler, J;van Oosterom, A T;Buytaert, P;Van Marck, E
通讯作者：
Van Marck, E
影响因子：
11.2
作者：
Bicaku, Elona;Marchion, Douglas C.;Munster, Pamela N.
通讯作者：
Munster, Pamela N.
影响因子：
45.3
作者：
Gutierrez, MC;Detre, S;Dowsett, M
通讯作者：
Dowsett, M
DOI：
10.1007/bf02967635
发表时间：
2003-01-01
期刊：
Breast cancer (Tokyo, Japan)
影响因子：
--
作者：
Kurebayashi, Junichi
通讯作者：
Kurebayashi, Junichi
影响因子：
5.6
作者：
Mandal, Soma;Davie, James R.
通讯作者：
Davie, James R.