Abnormal DNA methylation orchestrates many of the cancer‐related gene expression irregularities such as the inactivation of tumour suppressor genes through hypermethylation as well as activation of prometastatic genes through hypomethylation. The fact that DNA methylation abnormalities can be chemically reversed positions the DNA methylation machinery as an attractive target for anti‐cancer drug development. However, although in vitro studies suggested that targeting concordantly hypo‐ and hypermethylation is of benefit in suppressing both oncogenic and prometastatic functions of breast cancer cells, this has never been tested in a therapeutic setting in vivo. In this context, we investigated the combined therapeutic effects of an approved nutraceutical agent S‐adenosylmethionine (SAM) and FDA‐approved hypomethylating agent decitabine using the MDA‐MB‐231 xenograft model of breast cancer and found a pronounced reduction in mammary tumour volume and lung metastasis compared to the animals in the control and monotherapy treatment arms. Immunohistochemical assessment of the primary breast tumours showed a significantly reduced expression of proliferation (Ki‐67) and angiogenesis (CD31) markers following combination therapy as compared to the control group. Global transcriptome and methylome analyses have revealed that the combination therapy regulates genes from several key cancer‐related pathways that are abnormally expressed in breast tumours. To our knowledge, this is the first preclinical study demonstrating the anti‐cancer therapeutic potential of using a combination of methylating (SAM) and demethylating agent (decitabine) in vivo. Results from this study provide a molecularly founded rationale for clinically testing a combination of agents targeting the epigenome to reduce the morbidity and mortality from breast cancer.

中文翻译：

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S-腺苷甲硫氨酸联合地西他滨在抑制乳腺癌的生长和转移方面显示出增强的抗癌作用。

DNA甲基化异常会导致许多与癌症相关的基因表达异常，例如通过高甲基化使抑癌基因失活以及通过低甲基化激活前转移基因。DNA甲基化异常可以化学逆转的事实使DNA甲基化机制成为抗癌药物开发的有吸引力的靶标。然而，尽管体外研究表明一致地靶向低甲基化和高甲基化在抑制乳腺癌细胞的致癌和促转移功能方面均是有益的，但从未在体内的治疗环境中对其进行过测试。在这种情况下，我们使用MDA-MB-231乳腺癌异种移植模型研究了批准的营养药物S-腺苷甲硫氨酸（SAM）和FDA批准的次甲基化地西他滨的联合治疗效果，发现与相比，乳腺癌的乳腺肿瘤体积和肺转移明显减少控制和单一疗法治疗组中的动物。对原发性乳腺肿瘤的免疫组织化学评估显示，与对照组相比，联合治疗后增殖（Ki-67）和血管生成（CD31）标志物的表达明显降低。全球转录组和甲基化组分析表明，联合治疗可调节几种主要与癌症相关的途径的基因，这些基因在乳腺癌中异常表达。据我们所知，这是首次临床前研究，证明了在体内使用甲基化（SAM）和去甲基化剂（地西他滨）的组合具有的抗癌治疗潜力。这项研究的结果为临床测试靶向表观基因组的药物组合降低了乳腺癌的发病率和死亡率提供了分子基础的理论依据。