The roles of TRIM24 in breast cancer

项目总结 乳腺癌是一种致命的疾病，需要新的战略来实现治疗和治疗的目标 根除。表观遗传学抑制剂的最新发展为潜在的治疗提供了新的途径 治疗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，该模型与 将利用TRIM24在所有乳腺癌亚型中的异常表达来更深入地了解 肿瘤的发展和治疗。表观遗传调控是异常调控的常见目标， 所有人类癌症中的扩增或突变。组蛋白“作者”、“橡皮”和“读者”是表观遗传。 分别催化加成、去除和/或与翻译后修饰相互作用的调节子 组蛋白或其他修饰蛋白的(PTM)，以及随后对基因表达的调控结果。我们的 实验室发现了三方基序蛋白24(TRIM24)作为组蛋白阅读器，并表明TRIM24：(I) 泛素化的P53和TRIM24的siRNA耗尽导致胚胎干细胞依赖于P53的凋亡 乳腺癌来源细胞(MCF7)，(Ii)通过PhD/溴结构域阅读将雌激素受体募集到染色质 组蛋白PTMS(H3K4me0；H3K23ac)的独特特征共同调节雌激素依赖的转录， (Iii)通过改变代谢诱导永生化人乳腺上皮细胞(IHMEC)转化 当异位表达时上调c-Myc的表达，以及(Iv)一种小分子抑制物 TRIM24溴域在体外干扰染色质相互作用。重要的是，我们发现异常表达 TRIM24的表达与乳腺癌患者的生存期呈负相关。TRIM24在所有子类型中都过度表达 乳腺癌的发病率最高，在基底乳腺癌中最高。我们建立了一种表达TRIM24的小鼠模型 在乳腺上皮中有条件地过表达Trim24转基因导致的乳腺癌。我们看到了 TRIM24的异常、组织特异性表达足以促进肿瘤的发生、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TRIM24的异常表达 推动乳腺/乳房上皮异质性肿瘤的发展，我们的发现将进一步 表观遗传学治疗乳腺癌的研究进展。我们的长期目标是利用 深入理解TRIM24的作用机制，为乳房治疗提供新的治疗方法 以及人类的其他癌症。

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.