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Transcriptional repression in cancer gene therapy:targeting HER-2eu overexpression as an example

机译:癌症基因治疗中的转录抑制:以HER-2 / neu过表达为例

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Overexpression of the HER-2eu oncogene has been well-documented as a frequent event in human cancers. In clinic, overexpression of HER-2eu indicates a unfavorable prognosis and highly correlated with the low survival rate of patients associated with breast and ovarian cancers. Downregulation of the HER-2eu gene expression in cancer cells by attenuating the promoter activity of the gene is therefore an attractive strategy to reverse the transformation phenotype induced by HER-2eu overexpression. We have identified a number of cellular and viral transcriptional regulators, including the ets family member PEA3, the SV40 large T antigen, and the adenovirus type 5 E1A, which are able to repress the HER-2eu gene expression. Expression of these transcriptional regulators resulted in downregulation of the HER-2eu promoter activity and reversed the malignant phenotype of the transformed cells in vitro. These observations were followed by a series of studies to investigate whether these HER-2eu repressors can act therapeutically as tumor suppressor genes for cancers that overexpress HER-2eu. The growth of tumors derived from HER-2eu-overexpressing cancer cells was inhibited by the transcriptional repressors, accompanied by decreased HER-2eu expression in tumor cells. The results of these preclinical studies clearly indicate that transcriptional repressors which downregulate HER-2eu can be a promising regimen for cancer treatment in a gene therapy format.
机译:HER-2 / neu癌基因的过表达已被证明是人类癌症中的常见事件。在临床上,HER-2 / neu的过表达表明预后不良,并且与乳腺癌和卵巢癌患者的低生存率高度相关。因此,通过减弱基因的启动子活性来下调癌细胞中HER-2 / neu基因的表达是逆转由HER-2 / neu过表达诱导的转化表型的有吸引力的策略。我们已经确定了许多细胞和病毒的转录调节因子,包括ets家族成员PEA3,SV40大T抗原和5型腺病毒E1A,它们能够抑制HER-2 / neu基因的表达。这些转录调节因子的表达导致HER-2 / neu启动子活性的下调,并在体外逆转了转化细胞的恶性表型。这些观察结果之后,进行了一系列研究,以研究这些HER-2 / neu阻遏物是否可以作为过度表达HER-2 / neu的癌症的肿瘤抑制基因发挥治疗作用。转录阻遏物抑制源自HER-2 / neu过表达的癌细胞的肿瘤的生长,并伴随着肿瘤细胞中HER-2 / neu表达的降低。这些临床前研究的结果清楚地表明,下调HER-2 / neu的转录阻遏物可能是一种有前途的基因治疗癌症方案。

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