Suppression of breast tumor growth and metastasis by an engineered transcription factor.
Suppression of breast tumor growth and metastasis by an engineered transcription factor.
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DOI：
10.1371/journal.pone.0024595
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Blancafort P
中科院分区：
文献类型：
--
作者：
Beltran AS;Russo A;Lara H;Fan C;Lizardi PM;Blancafort P
Maspin是一种肿瘤和转移抑制因子，作为肿瘤进展的守门人发挥重要作用。它在上皮细胞中高度表达，但在转移性疾病的发病中通过表观遗传机制沉默。Maspin表观遗传沉默的重编程提供了锁定转移进展的治疗潜力。在此，我们研究了人工转录因子126（ATF-126）在免疫缺陷小鼠中上调Maspin启动子以抑制预先建立的乳腺肿瘤中的肿瘤进展的能力。ATF-126在侵袭性、间充质样和三阴性乳腺癌系MDA-MB-231中转导。多西环素在体内诱导ATF表达导致肿瘤生长减少50%，并完全消除肿瘤细胞定植。ATF诱导的细胞的全基因组转录谱揭示了在雌激素受体阳性（ER+）“正常样”内在亚型乳腺癌和侵袭性差的ER+管腔A乳腺癌细胞系中过度表达的基因特征。ATF-126和Maspin cDNA的比较转录谱定义了重叠的19个基因签名，包括Maspin信号级联下游的新靶点。我们的数据表明，Maspin上调了在乳腺癌中沉默的下游肿瘤和转移抑制基因，这些基因通常在神经系统中表达，包括CARNS 1，SLC 8A 2和DACT 3。此外，ATF-126和Maspin cDNA诱导导致也在神经细胞中表达的肿瘤抑制性miRNA（如miR-1和miR-34）的再活化，以及潜在致癌性miRNA（如miR-10 b、miR-124和miR-363）的下调。正如其在ER+肿瘤中的过度表达所预期的那样，ATF-126基因特征预测了乳腺癌患者的良好预后。我们的研究结果首次描述了ATF能够通过表观遗传学重新激活休眠的、正常样的和更分化的基因程序来减少肿瘤生长和转移性定植。
Maspin is a tumor and metastasis suppressor playing an essential role as gatekeeper of tumor progression. It is highly expressed in epithelial cells but is silenced in the onset of metastatic disease by epigenetic mechanisms. Reprogramming of Maspin epigenetic silencing offers a therapeutic potential to lock metastatic progression. Herein we have investigated the ability of the Artificial Transcription Factor 126 (ATF-126) designed to upregulate the Maspin promoter to inhibit tumor progression in pre-established breast tumors in immunodeficient mice. ATF-126 was transduced in the aggressive, mesenchymal-like and triple negative breast cancer line, MDA-MB-231. Induction of ATF expression in vivo by Doxycycline resulted in 50% reduction in tumor growth and totally abolished tumor cell colonization. Genome-wide transcriptional profiles of ATF-induced cells revealed a gene signature that was found over-represented in estrogen receptor positive (ER+) “Normal-like” intrinsic subtype of breast cancer and in poorly aggressive, ER+ luminal A breast cancer cell lines. The comparison transcriptional profiles of ATF-126 and Maspin cDNA defined an overlapping 19-gene signature, comprising novel targets downstream the Maspin signaling cascade. Our data suggest that Maspin up-regulates downstream tumor and metastasis suppressor genes that are silenced in breast cancers, and are normally expressed in the neural system, including CARNS1, SLC8A2 and DACT3. In addition, ATF-126 and Maspin cDNA induction led to the re-activation of tumor suppressive miRNAs also expressed in neural cells, such as miR-1 and miR-34, and to the down-regulation of potential oncogenic miRNAs, such as miR-10b, miR-124, and miR-363. As expected from its over-representation in ER+ tumors, the ATF-126-gene signature predicted favorable prognosis for breast cancer patients. Our results describe for the first time an ATF able to reduce tumor growth and metastatic colonization by epigenetic reactivation of a dormant, normal-like, and more differentiated gene program.
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