Caccuri Francesca, Sommariva Michele, Marsico Stefania, Giordano Francesca, Zani Alberto, Giacomini Arianna, Fraefel Cornel, Balsari Andrea, Caruso Arnaldo
Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy.
Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan 20133, Italy.
Cancers (Basel). 2019 Jul 18;11(7):1006. doi: 10.3390/cancers11071006.
Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers. In spite of initial good response to chemotherapy, the prognosis of TNBC remains poor and no effective specific targeted therapy is readily available. Recently, we demonstrated the ability of U94, the latency gene of human herpes virus 6 (HHV-6), to interfere with proliferation and with crucial steps of the metastatic cascade by using MDA-MB 231 TNBC breast cancer cell line. U94 expression was also associated with a partial mesenchymal-to-epithelial transition (MET) of cells, which displayed a less aggressive phenotype. In this study, we show the ability of U94 to exert its anticancer activity on three different TNBC cell lines by inhibiting DNA damage repair genes, cell cycle and eventually leading to cell death following activation of the intrinsic apoptotic pathway. Interestingly, we found that U94 acted synergistically with DNA-damaging drugs. Overall, we provide evidence that U94 is able to combat tumor cells with different mechanisms, thus attesting for the great potential of this molecule as a multi-target drug in cancer therapy.
三阴性乳腺癌（TNBC）占所有乳腺癌的15%-20%。尽管对化疗最初有良好反应，但TNBC的预后仍然很差，且尚无有效的特异性靶向治疗方法。最近，我们利用MDA-MB 231三阴性乳腺癌细胞系证明了人类疱疹病毒6型（HHV-6）的潜伏基因U94能够干扰细胞增殖以及转移级联反应的关键步骤。U94的表达还与细胞的部分间充质-上皮转化（MET）相关，这些细胞表现出侵袭性较小的表型。在本研究中，我们展示了U94通过抑制DNA损伤修复基因、细胞周期，并最终在激活内源性凋亡途径后导致细胞死亡，从而对三种不同的三阴性乳腺癌细胞系发挥抗癌活性的能力。有趣的是，我们发现U94与DNA损伤药物具有协同作用。总体而言，我们提供的证据表明，U94能够通过不同机制对抗肿瘤细胞，从而证明该分子作为癌症治疗中的多靶点药物具有巨大潜力。
