Targeting MCM2 function as a novel strategy for the treatment of highly malignant breast tumors.
Targeting MCM2 function as a novel strategy for the treatment of highly malignant breast tumors.
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DOI：
10.18632/oncotarget.5408
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发表时间：
2015-10-27
期刊：
影响因子：
--
通讯作者：
Kitagawa M
中科院分区：
文献类型：
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作者：
Abe S;Yamamoto K;Kurata M;Abe-Suzuki S;Horii R;Akiyama F;Kitagawa M
高度恶性肿瘤表达高水平的微型染色体维持2（MCM2）蛋白，这与晚期肿瘤分级、晚期和不良预后相关。在之前的一项研究中，我们发现，当 FLV 感染的造血细胞表达高水平的 MCM2 时，弗兰德白血病病毒 (FLV) 包膜蛋白 gp70 与 MCM2 结合，损害其核转位，并增强 DNA 损伤诱导的细胞凋亡。在这里，我们发现MCM2在乳腺癌的临床样本中高表达，尤其是三阴性乳腺癌（TNBC），以及在癌症干细胞（CSC）标记物阳性乳腺癌细胞中。为了使用 gp70 生成癌症治疗模型，我们通过将 Hph-1 的蛋白转导域 (PTD) 与 gp70 (Hph-1-gp70) 缀合，将 gp70 蛋白引入表达高水平 MCM2 的小鼠乳腺癌细胞的细胞质中。 Hph-1-gp70 已成功转导至乳腺癌细胞的细胞质中。转导蛋白在体外和体内增强了 DNA 损伤诱导的癌细胞凋亡。因此，使用 Hph-1-gp70 治疗诱导 DNA 损伤的 MCM2 靶向策略可能是治疗高度恶性乳腺癌（如 TNBC）和从乳腺癌组织中根除 CSC 样细胞的成功疗法。
Highly malignant tumors express high levels of the minichromosome maintenance 2 (MCM2) protein, which is associated with advanced tumor grade, advanced stage, and poor prognosis. In a previous study, we showed that Friend leukemia virus (FLV) envelope protein gp70 bound MCM2, impaired its nuclear translocation, and enhanced DNA-damage-induced apoptosis in FLV-infected hematopoietic cells when the cells expressed high levels of MCM2. Here, we show that MCM2 is highly expressed in clinical samples of invasive carcinoma of the breast, especially triple-negative breast cancer (TNBC), and in cancer stem cell (CSC) marker-positive breast cancer cells. To generate a cancer therapy model using gp70, we introduced the gp70 protein into the cytoplasm of murine breast cancer cells that express high levels of MCM2 by conjugating the protein transduction domain (PTD) of Hph-1 to gp70 (Hph- 1-gp70). Hph-1-gp70 was successfully transduced into the cytoplasm of breast cancer cells. The transduced protein enhanced the DNA damage-induced apoptosis of cancer cells in vitro and in vivo. Therefore, an MCM2-targeted strategy using Hph-1-gp70 treatment to induce DNA damage might be a successful therapy for highly malignant breast cancers such as TNBC and for the eradication of CSC-like cells from breast cancer tissue.