A Role for Histone H2B Variants in Endocrine-Resistant Breast Cancer.
A Role for Histone H2B Variants in Endocrine-Resistant Breast Cancer.
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DOI：
10.1007/s12672-015-0230-5
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发表时间：
2015-12
影响因子：
3
通讯作者：
Oesterreich S
中科院分区：
文献类型：
--
作者：
Nayak SR;Harrington E;Boone D;Hartmaier R;Chen J;Pathiraja TN;Cooper KL;Fine JL;Sanfilippo J;Davidson NE;Lee AV;Dabbs D;Oesterreich S
对芳香化酶抑制剂（AIs）的获得性耐药仍然是治疗雌激素受体阳性（ER+）乳腺癌的主要临床问题。我们和其他人以前曾报道过使用乳腺癌细胞系内分泌抵抗模型的DNA甲基化的广泛变化。在这里，我们表明，组蛋白变体HIST 1H 2BE是低甲基化的雌激素剥夺耐药C4-12和长期雌激素剥夺（LTED）细胞与亲本MCF-7细胞相比。正如所预期的，这种低甲基化与C4-12和LTED细胞中HIST 1H 2BE的表达增加有关。HIST 1H 2BE的过表达和下调均导致乳腺癌细胞系增殖降低，表明需要严格控制该组蛋白变体的表达。基因表达分析显示，在一个大的面板的乳腺癌细胞系中的HIST 1H 2BE的不同表达，不限于特定的分子亚型。ER+ AI治疗的乳腺肿瘤中HIST 1H 2BE信使RNA（mRNA）表达的分析显示，与敏感（n=37）肿瘤相比，耐药（n=19）肿瘤中的表达显著更高（p=0.01）。使用nanostring分析，我们测量了内分泌抵抗和内分泌敏感肿瘤中所有61种组蛋白变体的表达。我们发现在对AI治疗有抵抗力的肿瘤中有22种变异组蛋白基因的显著过表达。计算机模拟癌症基因组图谱（TCGA）分析显示HIST 1基因座频繁扩增。总之，我们的研究首次表明，组蛋白变体的过表达可能在ER+乳腺癌的内分泌反应中很重要，并且过表达至少部分是通过表观遗传机制和扩增介导的。未来的内分泌反应研究应该包括这些目前研究不足的组蛋白变体的潜在作用。
Acquired resistance to aromatase inhibitors (AIs) remains a major clinical problem in the treatment of estrogen receptor-positive (ER+) breast cancer. We and others have previously reported widespread changes in DNA methylation using breast cancer cell line models of endocrine resistance. Here, we show that the histone variant HIST1H2BE is hypomethylated in estrogen deprivation-resistant C4-12 and long-term estrogen-deprived (LTED) cells compared with parental MCF-7 cells. As expected, this hypomethylation associates with increased expression of HIST1H2BE in C4-12 and LTED cells. Both overexpression and downregulation of HIST1H2BE caused decreased proliferation in breast cancer cell lines suggesting the need for tightly controlled expression of this histone variant. Gene expression analysis showed varied expression of HIST1H2BE in a large panel of breast cancer cell lines, without restriction to specific molecular subtypes. Analysis of HIST1H2BE messenger RNA (mRNA) expression in ER+ AI-treated breast tumors showed significantly higher expression in resistant (n=19) compared with sensitive (n=37) tumors (p=0.01). Using nanostring analysis, we measured expression of all 61 histone variants in endocrine-resistant and endocrine-sensitive tumors. We found significant overexpression of 22 variant histone genes in tumors resistant to AI therapy. In silico The Cancer Genome Atlas (TCGA) analysis showed frequent amplification of the HIST1 locus. In summary, our studies show, for the first time, that overexpression of histone variants might be important in endocrine response in ER+ breast cancer, and that overexpression is at least in part mediated via epigenetic mechanisms and amplifications. Future studies addressing endocrine response should include a potential role of these currently understudied histone variants.