Department of Molecular and Cellular Biochemistry, Center for Biostatistics, College of Public Health, and Tumor Microenvironment Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
Cancer Res. 2010 Feb 15;70(4):1323-33. doi: 10.1158/0008-5472.CAN-09-1474. Epub 2010 Feb 9.
Tumor-associated macrophages (TAM) are implicated in breast cancer metastasis, but relatively little is known about the underlying genes and pathways that are involved. The transcription factor Ets2 is a direct target of signaling pathways involved in regulating macrophage functions during inflammation. We conditionally deleted Ets in TAMs to determine its function at this level on mouse mammary tumor growth and metastasis. Ets2 deletion in TAMs decreased the frequency and size of lung metastases in three different mouse models of breast cancer metastasis. Expression profiling and chromatin immunoprecipitation assays in isolated TAMs established that Ets2 repressed a gene program that included several well-characterized inhibitors of angiogenesis. Consistent with these results, Ets2 ablation in TAMs led to decreased angiogenesis and decreased growth of tumors. An Ets2-TAM expression signature consisting of 133 genes was identified within human breast cancer expression data which could retrospectively predict overall survival of patients with breast cancer in two independent data sets. In summary, we identified Ets2 as a central driver of a transcriptional program in TAMs that acts to promote lung metastasis of breast tumors.
肿瘤相关巨噬细胞(TAM)被认为与乳腺癌转移有关,但对于涉及的潜在基因和途径知之甚少。转录因子 Ets2 是参与调节炎症期间巨噬细胞功能的信号通路的直接靶标。我们条件性地在 TAMs 中缺失 Ets2,以确定其在小鼠乳腺肿瘤生长和转移中的功能。在三种不同的乳腺癌转移小鼠模型中,TAMs 中 Ets2 的缺失减少了肺转移的频率和大小。在分离的 TAMs 中进行的表达谱和染色质免疫沉淀分析表明,Ets2 抑制了一个包含几种已被充分鉴定的血管生成抑制剂的基因程序。与这些结果一致,TAMs 中 Ets2 的缺失导致血管生成减少和肿瘤生长减少。在人类乳腺癌表达数据中确定了一个由 133 个基因组成的 Ets2-TAM 表达特征,该特征可在两个独立的数据集回顾性预测乳腺癌患者的总生存率。总之,我们确定 Ets2 是 TAMs 中促进乳腺癌肺转移的转录程序的核心驱动因素。
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