CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3
CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3
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DOI：
10.1038/s41388-019-0739-0
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发表时间：
2019-06-06
期刊：
影响因子：
8
通讯作者：
Mollenhauer, Jan
中科院分区：
文献类型：
--
作者：
Block, Ines;Mueller, Carolin;Mollenhauer, Jan
乳腺癌是一种异质性遗传疾病，由每个肿瘤的个体突变累积驱动。全基因组测序方法已经鉴定出原发性肿瘤中具有复发性突变的许多基因。虽然在这些集合中，肿瘤抑制基因和癌基因的突变被过度描述，但大多数基因改变的基因在乳腺癌进展中的作用迄今为止尚不清楚。为了提高对复杂疾病乳腺癌的基本理解，并潜在地识别已知癌症驱动途径的新型药物靶标或调节剂，我们使用一系列构建的MCF 7细胞系分析了86个野生型基因和94个突变变体对细胞生长的影响。我们在随后的实验中证明，金属阳离子转运蛋白CNNM 4通过诱导细胞凋亡来调节生长，并在体外和体内确定了补体因子备解素（CFP）的肿瘤抑制作用。CFP似乎诱导与内质网应激反应相关的促凋亡转录因子DDIT 3的细胞内上调。
Breast cancer is a heterogeneous genetic disease driven by the accumulation of individual mutations per tumor. Whole-genome sequencing approaches have identified numerous genes with recurrent mutations in primary tumors. Although mutations in well characterized tumor suppressors and oncogenes are overrepresented in these sets, the majority of the genetically altered genes have so far unknown roles in breast cancer progression. To improve the basic understanding of the complex disease breast cancer and to potentially identify novel drug targets or regulators of known cancer-driving pathways, we analyzed 86 wild-type genes and 94 mutated variants for their effect on cell growth using a serially constructed panel of MCF7 cell lines. We demonstrate in subsequent experiments that the metal cation transporter CNNM4 regulates growth by induction of apoptosis and identified a tumor suppressive role of complement factor properdin (CFP) in vitro and in vivo. CFP appears to induce the intracellular upregulation of the pro-apoptotic transcription factor DDIT3 which is associated with endoplasmic reticulum-stress response.