The roles of TRIM24 in breast cancer

项目摘要 乳腺癌是一种致命的疾病，需要新的策略来实现治疗的目标， 根除基于表观遗传的抑制剂的最新发展提供了潜在治疗的新途径 用于乳腺癌和其他人类癌症。我们的工作使用了一种新的乳腺癌小鼠模型， TRIM 24在所有乳腺癌亚型中的异常表达将用于更深入地了解 肿瘤的发展和治疗。表观遗传调节因子是异常调节的常见目标， 在所有人类癌症中的扩增或突变。组蛋白的“书写者”、“擦除者”和“阅读者”是表观遗传的 分别催化添加、去除和/或与翻译后修饰相互作用的调节剂 组蛋白或其他修饰的蛋白质的PTMs，以及随后的基因表达调控结果。我们 一个实验室发现了三分基序蛋白24（TRIM 24）作为组蛋白阅读器，并表明TRIM 24：（i） 泛素化的p53和TRIM 24的siRNA缺失导致胚胎干细胞的p53依赖性凋亡， 乳腺癌衍生的细胞（MCF 7），（ii）通过PHD/布罗莫结构域阅读将雌激素受体募集到染色质 组蛋白PTMs（H3 K4 me 0; H3 K23 ac）的独特特征共同调节雌激素依赖性转录， (iii)通过改变代谢诱导永生化人乳腺上皮细胞（iHMEC）转化 并且当异位表达时上调c-Myc表达，和（iv）所述细胞的小分子抑制剂， TRIM 24布罗莫结构域在体外破坏染色质相互作用。重要的是，我们发现异常表达 TRIM 24的表达与乳腺癌患者的生存率呈负相关。TRIM 24在所有子类型中都过度表达 乳腺癌的发病率最高，在基底部乳腺癌中最高。我们开发了一种TRIM 24表达的小鼠模型， 通过在乳腺上皮中条件性过表达Trim 24转基因治疗乳腺癌。我们看到 TRIM 24的异常组织特异性表达足以使肿瘤发生、发展和进展， 高度异质性乳腺癌我们假设我们提出的多方面研究， 包括小鼠模型、培养细胞和体外分析，将揭示TRIM 24的异常表达是如何在细胞内表达的。 驱动乳腺/乳腺上皮异质性肿瘤的发展，我们的研究结果将进一步 开发基于表观遗传学的治疗方法来治疗乳腺癌。我们的长期目标是利用 对TRIM 24功能的深入机制理解有助于治疗乳腺癌的创新治疗方法 和其他癌症。

PROJECT SUMMARY Breast cancer is a deadly disease and new strategies are needed to fulfill the goals of treatment and eradication. Recent development of epigenetic-based inhibitors offers new avenues of potential therapeutics for breast and other human cancers. Our work using a new mouse model of breast cancer that parallels the aberrant expression of TRIM24 in all breast cancer sub-types will be used to gain a deeper understanding of tumor development and treatment. Epigenetic regulators are frequent targets of aberrant regulation, amplification or mutation in all human cancers. Histone “writers”, “erasers” and “readers” are epigenetic regulators that catalyze addition, removal and/or interaction, respectively, with post-translational modifications (PTMs) of histones or other modified proteins, with subsequent regulatory outcomes for gene expression. Our laboratory discovered Tripartite Motif Protein 24 (TRIM24) as a histone reader and showed that TRIM24: (i) ubiquitinated p53 and siRNA-depletion of TRIM24 led to p53-dependent apoptosis of embryonic stem cells and breast cancer-derived cells (MCF7), (ii) recruited estrogen receptor to chromatin by PHD/bromodomain reading of a unique signature of histone PTMs (H3K4me0; H3K23ac) to co-regulate estrogen-dependent transcription, (iii) induced transformation of immortalized human mammary epithelial cells (iHMECs) by altering metabolism and up-regulating c-Myc expression when ectopically expressed, and (iv) a small molecule inhibitor of the TRIM24 bromodomain disrupts chromatin interactions in vitro. Importantly, we found that aberrant expression of TRIM24 negatively correlates with breast cancer patient survival. TRIM24 is over expressed in all sub-types of breast cancer and is highest in basal breast cancers. We developed a mouse model of TRIM24-expressing breast cancers by conditional over-expression of a Trim24 transgene in mammary epithelia. We saw that aberrant, tissue-specific expression of TRIM24 is sufficient for tumor initiation, development and progression to highly heterogeneous mammary carcinomas. We hypothesize that our proposed, multi-faceted studies, including mouse models, cultured cells and in vitro analyses will uncover how aberrant expression of TRIM24 drives heterogeneous tumor development in mammary/breast epithelia, and that our findings will further development of epigenetic-based therapeutics to treat breast cancers. Our long-term goal is to leverage a deep mechanistic understanding of TRIM24 functions toward innovative therapeutic approaches to treat breast and other cancers in humans.