Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana.
Department of Obstetrics and Gynecology, Affiliated Hospital of Taishan Medical University, Taishan, Shandong, China.
Mol Cancer Res. 2017 Nov;15(11):1491-1502. doi: 10.1158/1541-7786.MCR-16-0297-T. Epub 2017 Jul 27.
Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERα in TNBC. KX-01 is a peptide substrate-targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-twice daily) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in nude mice that was correlated with Src kinase inhibition. KX-01 also increased ERα mRNA and protein, as well as increased the ERα targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1), and c-myc (MYC) in MDA-MB-231 and MDA-MB-468, but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, β-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERα targets pS2, cyclin D1, and c-myc. Chromatin immunoprecipitation (ChIP) of the ERα promoter in KX-01-treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERα promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERα expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen. Src kinase/pretubulin inhibitor KX-01 restores functional ERα expression in ERα breast tumors, a novel treatment strategy to treat triple-negative breast cancer. .
与雌激素受体-α（ERα）阳性的乳腺癌不同，三阴性乳腺癌（TNBC）没有靶向治疗方法。TNBC 中 ERα 的沉默是通过表观遗传改变（包括 DNA 甲基化和组蛋白乙酰化）实现的。恢复 TNBC 中 ERα 的表达可能使患者对内分泌治疗敏感。在乳腺癌中，c-Src 和 ERα 的表达呈负相关，这表明 c-Src 抑制可能导致 TNBC 中 ERα 的重新表达。KX-01 是一种在临床试验中用于实体瘤的肽底物靶向Src/微管蛋白抑制剂。KX-01（1mg/kg 体重，每日两次）抑制裸鼠中他莫昔芬耐药 MDA-MB-231 和 MDA-MB-157 TNBC 异种移植物的生长，这与 Src 激酶抑制相关。KX-01 还增加了 ERα mRNA 和蛋白，以及 ERα 靶孕激素受体（PR）、pS2（TFF1）、细胞周期蛋白 D1（CCND1）和 c-myc（MYC）在 MDA-MB-231 和 MDA-MB-468 中的表达，但不在 MDA-MB-157 异种移植物中。MDA-MB-231 和 MDA-MB-468 肿瘤中出现间充质标志物（波形蛋白、β-连环蛋白）减少和上皮标志物（E-钙黏蛋白）增加，提示发生间充质-上皮转化（MET）。KX-01 使 MDA-MB-231 和 MDA-MB-468 肿瘤对他莫昔芬生长抑制和他莫昔芬对 ERα 靶标 pS2、细胞周期蛋白 D1 和 c-myc 的抑制作用敏感。KX-01 处理的肿瘤中的 ERα 启动子的染色质免疫沉淀（ChIP）显示活性转录标记（乙酰化-H3、乙酰化-H3Lys9）的富集、HDAC1 的解离和 RNA 聚合酶 II 的募集。KX-01 对 ERα 启动子甲基化没有改变。这些数据表明，除了 Src 激酶抑制外，肽模拟物 KX-01 通过组蛋白乙酰化的改变恢复 TNBC 中的 ERα 表达，使肿瘤对他莫昔芬敏感。Src 激酶/微管蛋白抑制剂 KX-01 恢复 ERα 阳性乳腺癌中 ERα 的功能性表达，这是治疗三阴性乳腺癌的一种新的治疗策略。
