Role of the histone modifier MLL3 mutation in breast cancer cell plasticity

组蛋白修饰剂 MLL3 突变在乳腺癌细胞可塑性中的作用

• 批准号: 10579189
• 负责人: Wenjun Guo
• 金额: $ 37.66万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579189
• 关键词: Area; Breast Cancer Cell; Breast Cancer gene; Breast Epithelial Cells; CRISPR/Cas technology; Cancer Etiology; Carcinoma; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Data; Development; Endocrine; Enzymes; Epigenetic Process; Epithelial Cells; Epithelium; Experimental Models; Foundations; Gene Deletion; Gene Expression Regulation; Gene Proteins; Genetic; Goals; Histones; Homeostasis; Human; In Vitro; Induced Mutation; Knock-in Mouse; Knowledge; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Tumorigenesis; Mesenchymal; Methyltransferase; Modeling; Molecular; Multipotent Stem Cells; Mutate; Mutation; Neoplasm Metastasis; Oncogene Activation; Oncogenic; PIK3CG gene; Pathogenesis; Play; Point Mutation; Property; Protein Truncation; Research; Resistance; Role; Somatic Mutation; Stimulus; Technology; Testing; Therapeutic; Tissues; Tumor Promotion; Tumor Suppressor Proteins; cancer cell; cancer genome; cancer therapy; cancer type; epithelial to mesenchymal transition; genome editing; histone methyltransferase; hormone therapy; in vivo; innovation; malignant breast neoplasm; mammary; mammary epithelium; mutant; novel; stem cell differentiation; stem cell expansion; stem cells; stem-like cell; targeted cancer therapy; therapy resistant; tumor; tumor initiation; tumor progression; tumorigenesis

The discovery of frequent somatic mutations of epigenetic regulators in human cancers has highlighted a central role of epigenetic dysregulation in cancer pathogenesis. However, functions and mechanisms of action of these mutations remain largely unclear. The histone methyltransferase MLL3 (also known as KMT2C) is the most frequently mutated epigenetic regulator in breast cancer and also often altered in other major carcinomas. The majority of MLL3 mutations in breast cancer are gene deletion or protein-truncating point mutations. In addition, MLL3 expression is downregulated in breast cancers compared to normal breast tissues, suggesting it has a tumor suppressive role. Recent functional studies by us and others indeed have shown that MLL3 is an important tumor suppressor in different cancers. However, the mechanisms by which MLL3 mutations drive cancer pathogenesis remain poorly understood. Using novel tumor models that employ mammary stem cell (MaSC) and CRISPR technologies, we have shown that MLL3 deletion causes stem cell expansion and drives mammary tumorigenesis in cooperation with PI3K mutations, which significantly co-occur with MLL3 mutations in breast cancer. Our preliminary data also found that MLL3 mutation disrupted mammary epithelium homeostasis and induced multipotent stem cell activities in committed epithelial cell. Furthermore, we found MLL3 deletion sensitized cells to undergo epithelial- mesenchymal transition (EMT) in responding to various stimuli. These data suggest a role of MLL3 mutations in promoting cell plasticity in cancer development. EMT and related cell plasticity plays important role in cancer progression / metastasis and in therapeutic resistance. Consistently, we found MLL3 deletion greatly promoted tumor metastasis and resistance to endocrine therapy and PI3K inhibition in vivo. Based on these novel findings, we hypothesize that MLL3 mutation induces epithelial cell plasticity to promote tumorigenesis and metastasis and to confer resistance to cancer therapy. We will determine the role of MLL3 in regulating mammary epithelial cell plasticity during tissue homeostasis and oncogenic transformation (Aim 1), distinguish the role of MLL3 methyltransferase and adaptor functions in EMT and tumorigenesis (Aim 2), and determine the role of cell plasticity in MLL3 mutation-caused therapeutic resistance (Aim 3).

在人类癌症中发现表观遗传调节因子的频繁体细胞突变 强调了表观遗传失调在癌症发病机制中的核心作用。然而，在这方面， 这些突变的功能和作用机制仍然很不清楚。组蛋白 甲基转移酶MLL 3（也称为KMT 2C）是最常见的突变表观遗传 乳腺癌中的调节因子，并且在其他主要癌症中也经常改变。大多数MLL 3 乳腺癌中的突变是基因缺失或蛋白质截短点突变。此外，本发明还提供了一种方法， 与正常乳腺组织相比，乳腺癌中MLL 3表达下调， 表明它具有肿瘤抑制作用。我们和其他人最近的功能研究 已经表明MLL 3是不同癌症中的重要肿瘤抑制因子。但 MLL 3突变驱动癌症发病机制的机制仍然知之甚少。 使用采用乳腺干细胞（MaSC）和CRISPR的新型肿瘤模型 技术，我们已经表明，MLL 3缺失导致干细胞扩增和驱动， 与PI 3 K突变合作的乳腺肿瘤发生，PI 3 K突变与乳腺癌的发生显著共同发生。 乳腺癌中的MLL 3突变。我们的初步数据还发现MLL 3突变破坏了 乳腺上皮稳态和诱导的多能干细胞活性 上皮细胞此外，我们发现MLL 3缺失致敏细胞经历上皮- 间充质转化（EMT）在响应各种刺激。这些数据表明， MLL 3突变在癌症发展中促进细胞可塑性。EMT和相关细胞可塑性 在癌症进展/转移和治疗抗性中起重要作用。我们一贯认为， 我们发现MLL 3的缺失大大促进了肿瘤的转移和对内分泌治疗的抵抗 和体内PI 3 K抑制。 基于这些新的发现，我们假设MLL 3突变诱导上皮细胞 可塑性以促进肿瘤发生和转移并赋予对癌症治疗的抗性。 我们将确定MLL 3在组织培养过程中调节乳腺上皮细胞可塑性的作用。 稳态和致癌转化（目的1），区分MLL 3的作用 甲基转移酶和衔接子在EMT和肿瘤发生中的作用（Aim 2），并确定 细胞可塑性在MLL 3突变引起的治疗抗性中的作用（Aim 3）。